Neuroprotective electrical stimulation

ABSTRACT

Apparatus is provided that includes one or more electrodes, configured to be applied to a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesser palatine nerve, a sphenopalatine nerve, a communicating branch between a maxillary nerve and an SPG, an otic ganglion, an afferent fiber going into the otic ganglion, an efferent fiber going out of the otic ganglion, an infraorbital nerve, a vidian nerve, a greater superficial petrosal nerve, or a lesser deep petrosal nerve; and a control unit, configured to drive the electrodes to apply electrical stimulation to the site, and configure the stimulation to excite nervous tissue of the site at a strength sufficient to induce at least one neuroprotective occurrence selected from the group consisting of: an increase in cerebral blood flow (CBF), and a release of one or more neuroprotective substances, and insufficient to induce a significant increase in permeability of a blood-brain barrier (BBB).

CROSS-REFERENCES TO RELATED APPLICATIONS

The present application is a divisional of U.S. application Ser. No.13/223,929, filed Sep. 1, 2011, now U.S. Pat. No. 8,406,869, which is adivisional of U.S. application Ser. No. 11/465,381, filed Aug. 17, 2006,now U.S. Pat. No. 8,055,347, which claims the benefit of U.S.Provisional Application 60/709,734, filed Aug. 19, 2005, entitled,“Stimulation for treating brain events and other conditions,” which isassigned to the assignee of the present application and is incorporatedherein by reference, including the appendices thereof.

FIELD OF THE INVENTION BACKGROUND OF THE INVENTION

The blood-brain barrier (BBB) is a unique feature of the central nervoussystem (CNS) which isolates the brain from the systemic bloodcirculation. To maintain the homeostasis of the CNS, the BBB preventsaccess to the brain of many substances circulating in the blood.

The BBB is formed by a complex cellular system of endothelial cells,astroglia, pericytes, perivascular macrophages, and a basal lamina.Compared to other tissues, brain endothelia have the most intimatecell-to-cell connections: endothelial cells adhere strongly to eachother, forming structures specific to the CNS called “tight junctions”or zonula occludens. They involve two opposing plasma membranes whichform a membrane fusion with cytoplasmic densities on either side. Thesetight junctions prevent cell migration or cell movement betweenendothelial cells. A continuous uniform basement membrane surrounds thebrain capillaries. This basal lamina encloses contractile cells calledpericytes, which form an intermittent layer and probably play some rolein phagocytosis activity and defense if the BBB is breached. Astrocyticend feet, which cover the brain capillaries, build a continuous sleeveand maintain the integrity of the BBB by the synthesis and secretion ofsoluble growth factors (e.g., gamma-glutamyl transpeptidase) essentialfor the endothelial cells to develop their BBB characteristics.

PCT Publication WO 01/85094 and US Patent Application Publications2004/0015068 and 2004/0210269 to Shalev and Gross, which are assigned tothe assignee of the present patent application and are incorporatedherein by reference, describe apparatus for modifying a property of abrain of a patient, including electrodes applied to a sphenopalatineganglion (SPG) or a neural tract originating in or leading to the SPG. Acontrol unit drives the electrodes to apply a current capable ofinducing (a) an increase in permeability of a blood-brain barrier (BBB)of the patient, (b) a change in cerebral blood flow of the patient,and/or (c) an inhibition of parasympathetic activity of the SPG.

U.S. Pat. No. 6,853,858 to Shalev, which is assigned to the assignee ofthe present application and is incorporated herein by reference,describes apparatus for delivering a Non Steroidal Anti-InflammatoryDrug (NSAID) supplied to a body of a subject for delivery to at least aportion of a central nervous system (CNS) of the subject via a systemicblood circulation of the subject. The apparatus includes a stimulatoradapted to stimulate at least one site of the subject, so as to cause anincrease in passage of the NSAID from the systemic blood circulationacross a blood brain barrier (BBB) of the subject to the portion of theCNS, during at least a portion of the time that the NSAID is present inthe blood, the site selected from the group consisting of: asphenopalatine ganglion (SPG), an anterior ethmoidal nerve, a posteriorethmoidal nerve, a communicating branch between an anterior ethmoidalnerve and a retro-orbital branch of an SPG, a communicating branchbetween a posterior ethmoidal nerve and a retro-orbital branch of anSPG, a greater palatine nerve, a lesser palatine nerve, a sphenopalatinenerve, a communicating branch between a maxillary nerve and an SPG, anasopalatine nerve, a posterior nasal nerve, an infraorbital nerve, anotic ganglion, an afferent fiber going into the otic ganglion, anefferent fiber going out of the otic ganglion, a vidian nerve, a greatersuperficial petrosal nerve, and a lesser deep petrosal nerve.

US Patent Application Publication 2004/0220644 to Shalev et al., whichis assigned to the assignee of the present application and isincorporated herein by reference, describes a method for treating asubject, including positioning at least one electrode at least one siteof the subject, such as the SPG, for less than about 3 hours, applyingan electrical current to the site of the subject, and configuring thecurrent to increase cerebral blood flow (CBF) of the subject, so as totreat a condition of the subject.

US Patent Application Publication 2003/0176898 to Gross et al., which isassigned to the assignee of the present application and is incorporatedherein by reference, describes apparatus for treating a condition of aneye of a subject, comprising a stimulator adapted to stimulate at leastone site of the subject, such as the SPG, so as to treat the eyecondition.

US Patent Application Publication 2005/0159790 to Shalev, which isassigned to the assignee of the present application and is incorporatedherein by reference, describes a method for facilitating a diagnosis ofa condition of a subject, including applying a current to a site of thesubject, such as the SPG, and configuring the current to increaseconductance of molecules from brain tissue of the subject through ablood brain barrier (BBB) of the subject into a systemic bloodcirculation of the subject. The method also includes sensing a quantityof the molecules from a site outside of the brain of the subject,following initiation of application of the current.

US Patent Application Publication 2005/0266099 to Shalev, which isassigned to the assignee of the present application and is incorporatedherein by reference, describes a method for modifying a property of abrain of a patient includes presenting an odorant to an air passage ofthe patient, the odorant having been selected for presentation to theair passage because it is such as to increase conductance of moleculesfrom a systemic blood circulation of the patient through a blood brainbarrier (BBB) of the brain into brain tissue of the patient. Themolecules are selected from the group consisting of: a pharmacologicalagent, a therapeutic agent, an endogenous agent, and an agent forfacilitating a diagnostic procedure.

PCT Publication WO 04/010923 to Gross et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes a chemical agent delivery system, including achemical agent supplied to a body of a subject for delivery to a site ina central nervous system of said subject via blood of said subject; anda stimulator for stimulating parasympathetic fibers associated with theSPG, thereby rendering a blood brain barrier (BBB) of said subjectpermeable to said chemical agent during at least a portion of the timethat said chemical agent is present in said blood.

PCT Publication WO 04/043218 to Gross et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes apparatus for treating a subject, including (a) astimulation device, adapted to be implanted in a vicinity of a siteselected from the list consisting of: a SPG and a neural tractoriginating in or leading to the SPG; and (b) a connecting element,coupled to the stimulation device, and adapted to be passed through atleast a portion of a greater palatine canal of the subject.

PCT Publication WO 04/045242 to Shalev, which is assigned to theassignee of the present application and is incorporated herein byreference, describes apparatus for treating a condition of an ear of asubject, comprising a stimulator adapted to stimulate at least one siteof the subject, such as the SPG, at a level sufficient to treat the earcondition.

PCT Publication WO 05/030025 to Shalev et al., which is assigned to theassignee of the present application and is incorporated herein byreference, describes apparatus for treating a subject, including anelongated generally rigid support element having a length of at least1.8 cm, and having a distal end. The apparatus also includes one or moreelectrodes fixed to the support element in a vicinity of the distal endthereof, and configured to be positioned in a vicinity of a site of thesubject, such as the SPG, when the support element is inserted into abody of the subject, such that a portion of the support element remainsoutside of the body. The apparatus further includes a control unit,coupled to the support element, and adapted to drive the electrodes toapply an electrical current to the site, and to configure the current toincrease cerebral blood flow (CBF) of the subject, so as to treat acondition of the subject.

U.S. Pat. No. 6,526,318 to Ansarinia and related PCT Publication WO01/97905 to Ansarinia, which are incorporated herein by reference,describe a method for the suppression or prevention of various medicalconditions, including pain, movement disorders, autonomic disorders, andneuropsychiatric disorders. The method includes positioning an electrodeon or proximate to at least one of the patient's SPG, sphenopalatinenerves, or vidian nerves, and activating the electrode to apply anelectrical signal to such nerve. In a further embodiment for treatingthe same conditions, the electrode used is activated to dispense amedication solution or analgesic to such nerve.

U.S. Pat. No. 6,405,079 to Ansarinia, which is incorporated herein byreference, describes a method for the suppression or prevention ofvarious medical conditions, including pain, movement disorders,autonomic disorders, and neuropsychiatric disorders. The method includespositioning an electrode adjacent to or around a sinus, the duraadjacent a sinus, or falx cerebri, and activating the electrode to applyan electrical signal to the site. In a further embodiment for treatingthe same conditions, the electrode dispenses a medication solution oranalgesic to the site.

U.S. Pat. No. 6,432,986 to Levin and PCT Publication WO 99/03473 toLevin, which are incorporated herein by reference, describe techniquesfor inhibiting a cerebral neurovascular disorder or a muscular headache.The techniques include intranasally administering a pharmaceuticalcomposition comprising a long-acting local anesthetic.

U.S. Pat. No. 6,491,940 to Levin, US Patent Application 2003/0133877 toLevin, and PCT Publication WO 00/44432 to Levin, which are incorporatedherein by reference, describe techniques for inhibiting a cerebralneurovascular disorder or a muscular headache. The techniques includeintranasally administering a pharmaceutical composition comprising along-acting local anesthetic. Apparatus for delivering or applying thecomposition is also described.

US Patent Application 2001/0004644 to Levin and PCT Publication WO01/43733 to Levin, which are incorporated herein by reference, describetechniques for inhibiting cephalic inflammation, including meningealinflammation and cerebral inflammation. The techniques includeintranasally administering a long-acting local anesthetic. Apparatus fordelivering or applying the composition is also described, including adorsonasally implanted electronic neural stimulator, such as atransepithelial neural stimulation device.

The following patent application publications, all of which are assignedto the assignee of the present application and are incorporated hereinby reference, may be of interest: WO 03/090599, WO 03/105658, WO04/010923, WO 04/043218, WO 04/044947, WO 04/045242, WO 04/043217, WO04/043334, WO 05/030025, WO 05/030118, and US 2004/0220644.

The following patents and patent application publications, all of whichare incorporated herein by reference, may be of interest: U.S. Pat. No.5,756,071 to Mattern et al., U.S. Pat. No. 5,752,515 to Jolesz et al.,U.S. Pat. Nos. 5,725,471 and 6,086,525 to Davey et al., PCT PublicationWO 02/32504 to Zanger et al., US Patent Application Publication2003/0050527 to Fox et al., U.S. Pat. No. 6,415,184 to Ishikawa et al.,PCT Publications WO 03/084591, WO 03/020350, WO 03/000310, WO 02/068031,and WO 02/068029 to Djupesland, and US Patent Application Publication2003/0079742 to Giroux.

Hotta H et al., in an article entitled, “Effects of stimulating thenucleus basalis of Meynert on blood flow and delayed neuronal deathfollowing transient ischemia in rat cerebral cortes,” Jap J Phys52:383-393 (2002), which is incorporated herein by reference, reportthat stimulation of the nucleus basalis of Meynert (NBM) in the rat wasaccompanied by vasodilatation and increase in cortical blood flow. Theysuggest that NBM-originating vasodilative activation can protect theischemia-induced delayed death of cortical neurons by preventing a bloodflow decrease in widespread cortices.

Reis D J et al., in an article entitled, “Electrical stimulation ofcerebellar fastigial nucleus reduces ischemic infarction elicited bymiddle cerebral artery occlusion in rat,” J Cereb Blood Flow Metab11(5):810-8 (1991), which is incorporated herein by reference, reportthat electrical stimulation of the cerebellar fastigial nucleus (FN)profoundly increases cerebral blood flow via a cholinergic mechanism.Utilizing the rat middle cerebral artery occlusion (MCAO) model, theydemonstrated that one hour of electrical stimulation of the FN has thecapacity to substantially reduce the infarct size at the rim of thecortex dorsal and ventral to the infarction, and medially within thethalamus and striatum corresponding to the penumbral zone. They concludethat excitation of an intrinsic system in brain represented in therostral FN has the capacity to substantially reduce an ischemicinfarction.

Matsui T et al., in an article entitled, “The effects of cervical spinalcord stimulation (cSCS) on experimental stroke,” Pacing ClinElectrophysiol 12(4 Pt 2):726-32 (1989), which is incorporated herein byreference, report that cSCS increases regional cerebral blood flow, and,in a cat middle cerebral artery occlusion model (MCAO), reduced the rateof death within 24 hours after MCAO.

Segher O et al., in an article entitled, “Spinal cord stimulationreducing infract volume in model of focal cerebral ischemia in rats,” JNeurosurg 99(1):131-137 (2003), which is incorporated herein byreference, demonstrate that spinal cord stimulation increases cerebralblood flow in rats and significantly reduces stroke volume, suggestingthat spinal cord stimulation could be used for treatment and preventionof stroke.

The following references, which are incorporated herein by reference,may be useful:

Delepine L, Aubineau P, “Plasma protein extravasation induced in the ratdura mater by stimulation of the parasympathetic sphenopalatineganglion,” Experimental Neurology, 147, 389-400 (1997)

Hara H, Zhang Q J, Kuroyanagi T, Kobayashi S, “Parasympatheticcerebrovascular innervation: An anterograde tracing from thesphenopalatine ganglion in the rat,” Neurosurgery, 32, 822-827 (1993)

Jolliet-Riant P, Tillement J P, “Drug transfer across the blood-brainbarrier and improvement of brain delivery,” Fundam. Clin. Pharmacol.,13, 16-25 (1999)

Kroll R A, Neuwelt E A, “Outwitting the blood brain barrier fortherapeutic purposes: Osmotic opening and other means,” Neurosurgery,42, 1083-1100 (1998)

Syelaz J, Hara H, Pinard E, Mraovitch S, MacKenzie E T, Edvinsson L,“Effects of stimulation of the sphenopalatine ganglion on cortical bloodflow in the rat,” Journal of Cerebral Blood Flow and Metabolism,” 8,875-878 (1988)

Van de Waterbeemd H, Camenisch G, Folkers G, Chretien J R, Raevsky O A,“Estimation of blood brain barrier crossing of drugs using molecularsize and shape and h bonding descriptors,” Journal of Drug Targeting,”6, 151-165, (1998)

Suzuki N, Hardebo J E, Kahrstrom J, Owman C, “Selective electricalstimulation of postganglionic cerebrovascular parasympathetic nervefibers originating from the sphenopalatine ganglion enhances corticalblood flow in the rat,” Journal of Cerebral Blood Flow and Metabolism,10, 383-391 (1990)

Suzuki N, Hardebo J E, Kahrstrom J, Owman C H, “Effect on cortical bloodflow of electrical stimulation of trigeminal cerebrovascular nervefibres in the rat,” Acta Physiol. Scand., 138, 307-315 (1990)

Major A, Silver W, “Odorants presented to the rat nasal cavity increasecortical blood flow,” Chem. Senses, 24, 665-669 (1999)

Fusco B M, Fiore G, Gallo F, Martelletti P, Giacovazzo M,“‘Capsaicin-sensitive’ sensory neurons in cluster headache:pathophysiological aspects and therapeutic indications,” Headache, 34,132-137 (1994)

Lambert G A, Bogduk N, Goadsby P J, Duckworth J W, Lance J W, “Decreasedcarotid arterial resistance in cats in response to trigeminalstimulation,” Journal of Neurosurgery, 61, 307-315 (1984)

Silver W L, “Neural and pharmacological basis for nasal irritation,” inTucker W G, Leaderer B P, Mølhave L, Cain W S (eds), Sources of IndoorAir Contaminants, Ann. NY Acad. Sci., 641, 152-163 (1992)

Silver W, “Chemesthesis: the burning questions,” ChemoSense, Vol. 2, 1-2(1999)

Devoghel J C, “Cluster headache and sphenopalatine block,” ActaAnaesthesiol Belg., 32(1):101-7 (1981)

Branston N M, “The physiology of the cerebrovascular parasympatheticinnervation,” British Journal of Neurosurgery 9:319-329 (1995)

Branston N M et al., “Contribution of cerebrovascular parasympatheticand sensory innervation to the short-term control of blood flow in ratcerebral cortex,” J Cereb Blood Flow Metab 15(3):525-31 (1995)

Toda N et al., “Cerebral vasodilation induced by stimulation of thepterygopalatine ganglion and greater petrosal nerve in anesthetizedmonkeys,” Neuroscience 96(2):393-398 (2000)

Seylaz J et al., “Effect of stimulation of the sphenopalatine ganglionon cortical blood flow in the rat,” J Cereb Blood Flow Metab 8(6):875-8(1988)

Nollet H et al., “Transcranial magnetic stimulation: review of thetechnique, basic principles and applications,” The Veterinary Journal166:28-42 (2003)

Van Gijn J et al., “Subarachnoid haemorrhage: diagnosis, causes andmanagement,” Brain 124:249-278 (2001)

Goadsby P J et al., “Effect of stimulation of trigeminal ganglion onregional cerebral blood flow in cats,” Am J Physiol 22:R270-R274 (1987)

Walters B B et al., “Cerebrovascular projections from the sphenopalatineand otic ganglia to the middle cerebral artery of the cat,” Stroke17:488-494 (1986)

Suzuki N et al., “Trigeminal fibre collaterals storing substance P andcalcitonin gene-related peptide associate with ganglion cells containingcholine acetyltransferase and vasoactive intestinal polypeptide in thesphenopalatine ganglion of the rat. An axon reflex modulatingparasympathetic ganglionic activity?” Neuroscience 30:595-604 (1989)

Roth B J et al., “In vitro evaluation of a 4-leaf coil design formagnetic stimulation of peripheral nerve,” Electroencephalography andClinical Neurophysiology 93:68-74 (1994)

Zhang R et al., “A nitric oxide donor induces neurogenesis and reducesfunctional deficits after stroke in rats,” Ann Neurol 50:602-611 (2001)

Ziche M et al., “Nitric oxide and angiogenesis,” J Neurooncol 50:139-148(2000)

Kawamata T et al., “Intracisternal basic fibroblast growth factor (bFGF)enhances behavioral recovery following focal cerebral infarction in therat,” J Cereb Blood Flow Metab 16:542-547 (1996)

Zhang Z G et el., “VEGF enhances angiogenesis and promotes blood-brainbarrier leakage in the ischemic brain,” J Clin Invest 106:829-838 (2000)

Sun Y et al., “Neuronal nitric oxide synthase and ischemia-inducedneurogenesis,” J Cereb Blood Flow Metab 25(4):485-92 (2005)

Zhang F et al., “Nitric oxide donors increase blood flow and reducebrain damage in focal ischemia: evidence that nitric oxide is beneficialin the early stages of cerebral ischemia,” J Cereb Blood Flow Metab14(2):217-26 (1994)

Beridze M et al., “Effect of nitric oxide initial blood levels onerythrocyte aggregability during 12 hours from ischemic stroke onset,”Clin Hemorheol Microcirc 30(3-4):403-6 (2004)

Davis S M et al., “Advances in penumbra imaging with MR,” CerebrovascDis 17 Suppl 3:23-7 (2004)

Phan T G et al., “Salvaging the ischaemic penumbra: more than justreperfusion?” Clin Exp Pharmacol Physiol 29(1-2):1-10 (2002)

Gressens P et al., “Neuroprotection of the developing brain by systemicadministration of vasoactive intestinal peptide derivatives,” JPharmacol Exp Ther 288 (3):1207-13 (1999)

Zhang R et al., “Nitric oxide enhances angiogenesis via the synthesis ofvascular endothelial growth factor and cGMP after stroke in the rat,”Circ Res 21; 92(3):308-13 (2003)

de la Torre J C, “Vascular basis of Alzheimer's pathogenesis,” Ann NYAcad Sci 977:196-215 (2002)

Roman G C, “Cholinergic dysfunction in vascular dementia,” CurrPsychiatry Rep 7(1):18-26 (2005)

Tony J F L, “Nitric oxide and the cerebral vascular function,” J BiomedSci 7:16-26 (2000)

Pluta R M, “Delayed cerebral vasospasm and nitric oxide: review, newhypothesis, and proposed treatment,” Pharmacol Ther 105(1):23-56 (2005)

Sandgren K et al., “Vasoactive intestinal peptide and nitric oxidepromote survival of adult rat myenteric neurons in culture,” J NeurosciRes 72(5):595-602 (2003)

Laude K et al., “NO produced by endothelial NO synthase is a mediator ofdelayed preconditioning-induced endothelial protection,” Am J PhysiolHeart Circ Physiol 284(6):H2053-60 (2003) (Epub 2003 Jan. 9)

Khan M et al., “S-Nitrosoglutathione reduces inflammation and protectsbrain against focal cerebral ischemia in a rat model of experimentalstroke,” J Cereb Blood Flow Metab 25(2):177-92 (2005)

Molloy J et al., “S-nitrosoglutathione reduces the rate of embolizationin humans,” Circulation 98(14):1372-5 (1998)

Schmid-Elsaesser R et al., “A critical reevaluation of the intraluminalthread model of focal cerebral ischemia. Evidence of inadvertentpremature reperfusion and subarachnoid hemorrhage in rats bylaser-Doppler flowmetry,” Stroke 29:2162-2170 (1998)

Zausinger V S et al., “Neurological impairment in rats after transientmiddle cerebral artery occlusion: a comparative study under varioustreatment paradigms,” Brain Research 863(1-2):94-105 (2000)

Hunter A J et al., “To what extent have functional studies of ischemiain animals been useful in the assessment of potential neuroprotectiveagents?” Trends Pharmacol Sci 19:59-66 (1998)

Varghese et al., “Endoscopic transnasal neurolytic sphenopalatineganglion block for head and neck cancer pain,” J Laryngol Otol115(5):385-7 (2001)

Kanner A A et al., “Serum S100beta: a noninvasive marker of blood-brainbarrier function and brain lesions,” Cancer 97(11):2806-13 (2003)

SUMMARY OF THE INVENTION

In some embodiments of the present invention, an electrical stimulationsystem is provided for the treatment of an adverse brain condition, suchas an adverse cerebrovascular condition, e.g., an ischemic event. Thesystem is configured to apply excitatory electrical stimulation to atleast one “modulation target site” (MTS), as defined hereinbelow, suchas a sphenopalatine ganglion (SPG). The system configures thestimulation to dilate cerebral vessels, thereby increasing cerebralblood flow (CBF) to affected brain tissue and tissue in a vicinitythereof, and/or to induce the release of one or more neuroprotectivesubstances, such as neuromodulators (e.g., nitric oxide (NO) and/orvasoactive intestinal polypeptide (VIP)). Such increased CBF and/orrelease of neuroprotective substances decreases damage caused by thebrain condition. The stimulation system is generally useful for treatingbrain ischemia, such as caused by ischemic stroke or other brainconditions.

For some applications, the system is configured to perform acutetreatment of an adverse cerebrovascular event, such as ischemic stroke,by applying the stimulation within three hours of the stroke, while asignificant penumbra remains. Experiments conducted by the inventorshave demonstrated the efficacy of such acute treatment in an animalmodel. For other applications, the system is configured to performpost-acute treatment of ischemic stroke, by applying the stimulationmore than three hours after the stroke, when a significant penumbragenerally no longer remains. Experiments conducted by the inventors havedemonstrated the efficacy of such post-acute treatment in an animalmodel. For still other applications, the system is configured to applystimulation on a chronic, long-term basis, for at least one week, suchas at least two weeks, at least four weeks, at least three months, or atleast six months. During this chronic treatment, stimulation istypically applied intermittently, such as during one session per day.Experiments conducted by the inventors have demonstrated the efficacy ofsuch post-acute treatment in an animal model.

In some embodiments of the present invention, the system is configuredto perform staged treatment of an adverse brain event, such as acerebrovascular event, e.g., an ischemic stroke. The system isconfigured to adjust at least one parameter of the applied stimulationresponsively to an amount of time that has elapsed since the occurrenceof the brain condition. For some applications, during a first, acutestage, the system sets the parameters of stimulation at a first, highlevel, which is sufficient to cause a high level of cerebral vesseldilation and/or a release of neuroprotective substances, butinsufficient to induce a significant increase in permeability of theblood-brain barrier (BBB). Such stimulation is primarily intended toarrest the spreading of the initial ischemic core, such as by restoringblood flow to the penumbra in order to prevent damage to cells therein,and/or by releasing neuroprotective substances, such as NO and/or VIP.Such stimulation may also save some cells within the ischemic core, suchas neuronal cells. The first stage of stimulation is typicallyappropriate during the period beginning at the time of the event, andending at about 4 to 8 hours after the time of the event, such as atabout 6 hours after the event. Alternatively, the first stage ofstimulation is appropriate until about 24 hours after the time of theevent.

During a second, rehabilitative stage, the system reduces the strengthof the stimulation, and typically applies the stimulationintermittently, such as during one session per day, having a duration ofbetween about 2 and about 3 hours. (For some applications, the sessionhas a shorter duration, e.g., between about 0.5 and about 2 hours, or alonger duration, e.g., between about 3 and about 16 hours.) Thisrehabilitative level of stimulation generally continues to induce therelease of neuroprotective substances, and/or maintains a slightlyelevated level of blood flow to the brain. This stage of stimulation istypically applied during the period beginning at the conclusion of thefirst stage, and lasting at least one week, such as at least two weeks,at least one month, at least three months, or at least six months.

In the present patent application, a “modulation target site” (MTS)consists of:

-   -   an SPG (also called a pterygopalatine ganglion);    -   a nerve of the pterygoid canal (also called a vidian nerve),        such as a greater superficial petrosal nerve (a preganglionic        parasympathetic nerve) or a lesser deep petrosal nerve (a        postganglionic sympathetic nerve);    -   a greater palatine nerve;    -   a lesser palatine nerve;    -   a sphenopalatine nerve;    -   a communicating branch between the maxillary nerve and the        sphenopalatine ganglion;    -   an otic ganglion;    -   an afferent fiber going into the otic ganglion;    -   an efferent fiber going out of the otic ganglion; or    -   an infraorbital nerve.

In some embodiments of the present invention, an electrical stimulationsystem is configured to apply excitatory electrical stimulation to atleast one MTS of a subject, and to configure the stimulation to increaseCBF of the subject and/or induce the release of one or moreneuroprotective substances, such as neuromodulators (e.g., nitric oxide(NO) and/or vasoactive intestinal polypeptide (VIP)), withoutsignificantly opening the BBB of the subject. For some applications, thesystem sets a strength of the stimulation to less than 90% of theminimum strength necessary to begin significantly opening the BBB (the“minimum BBB-opening strength”), such as less than about 80%, about 70%,or about 60% of the minimum BBB-opening strength. For some applications,the system sets the strength of stimulation to a level appropriate forlong-term rehabilitation or prevention of a brain condition, such asbetween about 10% and about 40% of the minimum BBB-opening strength,e.g., between about 20% and about 30% of the minimum BBB-openingstrength. For other applications, the system sets the strength ofstimulation to a level appropriate for acute treatment of a brain event,such as at least about 20% of the minimum BBB-opening strength, e.g., atleast about 50%, 60%, 70%, or 80% of the minimum BBB-opening strength.

In some embodiments of the present invention, a method for treating abrain tumor comprises: (a) during a first period of time, applyingexcitatory electrical stimulation to at least one MTS at a first,relatively low strength, in conjunction with administration of achemotherapeutic drug at a first, relatively high dosage; and (b) duringa second period of time after the first period, applying the stimulationat a second strength greater than the first strength, in conjunctionwith administration of the drug at a second dosage lower than the firstdosage. Typically, stimulation at the first strength is sufficient toopen the blood-tumor barrier (BTB) in the core and tissue near the coreof the tumor, where the BTB has generally been damaged, but not in theperiphery of the tumor, where the BBB/BTB generally remainssubstantially intact. Stimulation at the second strength is typicallysufficient to open the BBB in the periphery of the tumor and throughoutthe brain.

In some embodiments of the present invention, the cerebrovascularcondition is caused by a cerebrovascular incident, such as stroke,aneurysm, or an arteriovenous malformation, or by ananoxic/hypoxic/ischemic event, such as anoxic brain injury caused bynear drowning, kidney failure, heart failure, chemical exposure,myocardial infarction, or electric shock. As used in the presentapplication, including in the claims, the phrase an “adversecerebrovascular event” includes, but is not limited to, acerebrovascular incident, such as stroke, aneurysm, or an arteriovenousmalformations, and an anoxic/hypoxic/ischemic event, such as anoxicbrain injury caused by near drowning, kidney failure, heart failure,chemical exposure, myocardial infarction, or electric shock. As used inthe present application, including in the claims, the phrases an“adverse cerebrovascular event” and an “adverse cerebrovascularcondition” exclude from their scope Alzheimer's disease and Parkinson'sdisease. Nevertheless, in some embodiments of the present invention, atleast some of the techniques described herein may be used for treatingthese two diseases.

In some embodiments of the present invention, chemical stimulation of atleast one MTS is achieved by presenting chemicals, for example in aliquid or gaseous state, to an air passage of the subject, such as anasal cavity or a throat, or in a vicinity thereof. The temporal profileand other quantitative characteristics of such chemical modulation arebelieved by the present inventors to have a mechanism of action that hasa neuroanatomical basis overlapping with that of the electricalmodulation of the MTS. For some applications, chemical-presentationtechniques described herein are practiced in combination with techniquesdescribed in PCT Patent Application PCT/IL03/00338, filed Apr. 25, 2003and/or a US patent application filed Sep. 27, 2005, entitled,“Stimulation for treating and diagnosing conditions,” both of which areassigned to the assignee of the present patent application and areincorporated herein by reference.

Chemicals that may increase or decrease cerebral blood flow and/or thepermeability of the blood-brain barrier (e.g., via modulation ofSPG-related fibers), include, but are not limited to, propionic acid,cyclohexanone, amyl acetate, acetic acid, citric acid, carbon dioxide,sodium chloride, ammonia, menthol, alcohol, nicotine, piperine,gingerol, zingerone, allyl isothiocyanate, cinnamaldehyde,cuminaldehyde, 2-propenyl/2-phenylethyl isothiocyanate, thymol, andeucalyptol. The chemicals reach the appropriate neural structures andinduce vasodilatation, vasoconstriction and/or cerebrovascularpermeability changes.

In some embodiments of the present invention, chemical stimulation isapplied to at least one MTS, using (a) a nasal applicator configured todeliver the stimulating chemical to an upper region of the nasal cavity,or (b) a transpalatine applicator inserted via the greater palatinecanal.

In some embodiments of the present invention, stimulation of the MTS isachieved by applying mechanical stimulation to the MTS, e.g., vibration.

In some embodiments of the present invention, stimulation of at leastone MTS is achieved by applying a neuroexcitatory agent to the MTS.Suitable neuroexcitatory agents include, but are not limited to,acetylcholine and urocholine. For some applications, the MTS isstimulated by applying a neuroinhibitory agent, such as atropine,hexamethonium, or a local anesthetic (e.g., lidocaine).

It is to be appreciated that references herein to specific modulationtarget sites are to be understood as including other modulation targetsites, as appropriate.

It is further to be appreciated that insertion and modulation sites,methods of insertion and/or implantation, and parameters of modulationare described herein by way of illustration and not limitation, and thatthe scope of the present invention includes other possibilities whichwould be obvious to someone of ordinary skill in the art who has readthe present patent application.

It is yet further to be appreciated that while some embodiments of theinvention are generally described herein with respect to electricaltransmission of power and electrical modulation of tissue, other modesof energy transport may be used as well. Such energy includes, but isnot limited to, direct or induced electromagnetic energy, radiofrequency(RF) transmission, mechanical vibration, ultrasonic transmission,optical power, and low power laser energy (via, for example, a fiberoptic cable).

It is additionally to be appreciated that whereas some embodiments ofthe present invention are described with respect to application ofelectrical currents to tissue, this is to be understood in the contextof the present patent application and in the claims as beingsubstantially equivalent to applying an electrical field, e.g., bycreating a voltage drop between two electrodes.

In embodiments of the present invention, treating an adverse brain eventor condition typically includes identifying that a subject is sufferingfrom, and/or has suffered from, the brain event or condition.

There is therefore provided, in accordance with an embodiment of thepresent invention, apparatus for treatment, including:

one or more electrodes, configured to be applied to a site of a subjectselected from the group consisting of: a sphenopalatine ganglion (SPG),a greater palatine nerve, a lesser palatine nerve, a sphenopalatinenerve, a communicating branch between a maxillary nerve and an SPG, anotic ganglion, an afferent fiber going into the otic ganglion, anefferent fiber going out of the otic ganglion, an infraorbital nerve, avidian nerve, a greater superficial petrosal nerve, and a lesser deeppetrosal nerve; and

adverse cerebrovascular condition treatment functionality, whichincludes a control unit configured to:

drive the one or more electrodes to apply electrical stimulation to thesite during a plurality of stimulation periods which includes at leastfirst and last stimulation periods,

set an inter-period interval between initiation of the first stimulationperiod and initiation of the last stimulation period to be at least 24hours, and

configure the stimulation during the first and last stimulation periodsto induce at least one neuroprotective occurrence selected from thegroup consisting of: an increase in cerebral blood flow (CBF) of thesubject, and a release of one or more neuroprotective substances.

For some applications, the control unit is configured to set theinter-period interval to be no more than a maximum value. For someapplications, the control unit is configured to set the inter-periodinterval to be no more than nine months.

In an embodiment, the control unit is configured to store a maximumtotal time of stimulation per each time period having a given duration,and to drive the one or more electrodes to apply the stimulation no morethan the maximum total time per each time period having the givenduration.

In an embodiment, the plurality of stimulation periods includes at leastone second stimulation period between the first and last stimulationperiods, and the control unit is configured to drive the one or moreelectrodes to apply the stimulation during the first, second, and laststimulation periods, and to configure the stimulation during the first,second, and last stimulation periods to induce the at least oneneuroprotective occurrence.

In an embodiment, the initiation of the last stimulation period occurssimultaneously with a conclusion of the first stimulation period, andthe control unit is configured to drive the one or more electrodes toapply the stimulation continuously from the initiation of the firststimulation period to a conclusion of the last stimulation period.Alternatively, the initiation of the last stimulation period occursafter a conclusion of the first stimulation period, and the control unitis configured to withhold driving the one or more electrodes to applythe stimulation during at least one non-stimulation period between theconclusion of the first stimulation period and the initiation of thelast stimulation period.

For some applications, the control unit is configured to drive the oneor more electrodes to apply the stimulation for between one and sixhours during each of the first and last stimulation periods.

For some applications, the control unit is configured to set a strengthof the stimulation during at least one of the plurality of stimulationperiods to be insufficient to induce a significant increase inpermeability of a blood-brain barrier (BBB) of the subject. For example,the control unit may be configured to set the strength of thestimulation during the at least one of the plurality of stimulationperiods to be less than 40% of a strength that is sufficient to inducethe significant increase in permeability of the BBB.

In an embodiment, the apparatus includes a user interface, which isconfigured to receive as input a treatment duration value, and thecontrol unit is configured to set the inter-period interval to be equalto the inputted treatment duration value. For some applications, thecontrol unit is configured to store a predetermined maximum treatmentduration value, and to compare the inputted treatment duration valuewith the maximum treatment duration value.

For some applications, the control unit is configured to set theinter-period interval to be at least 48 hours. For some applications,the control unit is configured to drive the one or more electrodes toapply the stimulation non-continuously during two or more of theplurality of the stimulation periods during each 24-hour period betweenthe initiation of the first stimulation period and the initiation of thelast stimulation period.

In an embodiment, the control unit is configured to set the inter-periodinterval to be at least one week. For some applications, the pluralityof stimulation periods includes a plurality of daily stimulationperiods, and the control unit is configured to drive the one or moreelectrodes to apply the stimulation during at least one of the dailystimulation periods on every day between the initiation of the firststimulation period and the initiation of the last stimulation period,and to configure the stimulation during the plurality of dailystimulation periods to induce the at least one neuroprotectiveoccurrence.

For some applications, the control unit is configured to drive the oneor more electrodes to apply the stimulation for at least 30 minutesevery day, such as at least 60 minutes every day, between the initiationof the first stimulation period and the initiation of the laststimulation period.

For some applications, the control unit is configured to set theinter-period interval to be at least two weeks, such as at least fourweeks.

For some applications, the control unit is configured to set a strengthof the stimulation during at least one of the plurality of stimulationperiods to be less than 40% of a strength that induces a maximumincrease in CBF in the subject that is achievable by applying thestimulation. Alternatively or additionally, for some applications, thecontrol unit is configured to set a strength of the stimulation duringat least one of the plurality of stimulation periods to a level thatinduces less than 40% of a maximum increase in CBF in the subject thatis achievable by applying the stimulation.

For some applications, the control unit is configured to drive the oneor more electrodes to apply the stimulation for less than six hoursduring each of the first and last stimulation periods.

In an embodiment, the site includes the SPG, and the one or moreelectrodes are configured to be applied to the SPG. For someapplications, the apparatus includes an elongated support elementconfigured to be placed within a greater palatine canal of the subject,sized to extend from a palate of the subject to the SPG, and having adistal end, and the electrodes are fixed to the support element in avicinity of the distal end thereof.

In an embodiment, the control unit is configured to drive the one ormore electrodes to apply the stimulation during the first period at afirst stimulation strength and during the last period at a secondstimulation strength, and to set the second stimulation strength to bedifferent from the first stimulation strength, such as less than orgreater than the first stimulation strength.

For some applications, the adverse cerebrovascular condition treatmentfunctionality includes stroke treatment functionality, such as ischemicstroke treatment functionality.

There is further provided, in accordance with an embodiment of thepresent invention, a method for treatment, including:

identifying that a subject suffers from an adverse cerebrovascularcondition;

responsively to the identifying, applying electrical stimulation to asite of the subject during a plurality of stimulation periods whichincludes at least first and last stimulation periods, the site selectedfrom the group consisting of: a sphenopalatine ganglion (SPG), a greaterpalatine nerve, a lesser palatine nerve, a sphenopalatine nerve, acommunicating branch between a maxillary nerve and an SPG, an oticganglion, an afferent fiber going into the otic ganglion, an efferentfiber going out of the otic ganglion, an infraorbital nerve, a vidiannerve, a greater superficial petrosal nerve, and a lesser deep petrosalnerve;

setting an inter-period interval between initiation of the firststimulation period and initiation of the last stimulation period to beat least 24 hours; and

configuring the stimulation during the first and last stimulationperiods to induce at least one neuroprotective occurrence selected fromthe group consisting of: an increase in cerebral blood flow (CBF) of thesubject, and a release of one or more neuroprotective substances.

In an embodiment, the adverse cerebrovascular condition includes anischemic stroke, and identifying that the subject suffers from thecondition includes identifying that the subject has experienced theischemic stroke. Alternatively, for some applications, the conditionincludes an aneurysm or an arteriovenous malformation, or an anoxicbrain injury caused, for example, by near drowning, kidney failure,heart failure, chemical exposure, myocardial infarction, or electricshock.

For some applications, applying the stimulation during the first andlast stimulation periods includes applying the stimulation for less thansix hours during each of the first and last stimulation periods.

In an embodiment, applying the stimulation includes placing anelectrical stimulator in a vicinity of the site, and activating thestimulator to apply the stimulation.

In an embodiment, the condition includes an adverse cerebrovascularevent, identifying that the subject suffers from the condition includesidentifying that the subject has experienced the event, and applying thestimulation includes applying the stimulation beginning at least threehours after the event, such as at least six hours after the event, atleast nine hours after the event, at least 12 hours after the event, orat least 24 hours after the event.

There is still further provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject, including:

one or more electrodes, configured to be applied to a site of thesubject selected from the group consisting of: a sphenopalatine ganglion(SPG), a greater palatine nerve, a lesser palatine nerve, asphenopalatine nerve, a communicating branch between a maxillary nerveand an SPG, an otic ganglion, an afferent fiber going into the oticganglion, an efferent fiber going out of the otic ganglion, aninfraorbital nerve, a vidian nerve, a greater superficial petrosalnerve, and a lesser deep petrosal nerve; and

a control unit, configured to:

drive the one or more electrodes to apply electrical stimulation to thesite, and

configure the stimulation to excite nervous tissue of the site at astrength sufficient to induce at least one neuroprotective occurrenceselected from the group consisting of: an increase in cerebral bloodflow (CBF) of the subject, and a release of one or more neuroprotectivesubstances, and insufficient to induce a significant increase inpermeability of a blood-brain barrier (BBB) of the subject.

In an embodiment, the control unit is configured to set the strength toless than 90% of a strength sufficient to induce the significantincrease in the permeability of the BBB. Alternatively or additionally,the control unit is configured to set the strength to less than 40% of astrength sufficient to induce the significant increase in thepermeability of the BBB.

For some applications, the control unit is configured to set thestrength to more than 50% of a strength sufficient to induce thesignificant increase in the permeability of the BBB.

In an embodiment, the site includes the SPG, and the electrodes areconfigured to be applied to the SPG. For some applications, theapparatus includes an elongated support element configured to be placedwithin a greater palatine canal of the subject, sized to extend from apalate of the subject to the SPG, and having a distal end, and theelectrodes are fixed to the support element in a vicinity of the distalend thereof.

There is additionally provided, in accordance with an embodiment of thepresent invention, apparatus for treating a subject, including:

one or more electrodes, configured to be applied to a site of thesubject selected from the group consisting of: a sphenopalatine ganglion(SPG), a greater palatine nerve, a lesser palatine nerve, asphenopalatine nerve, a communicating branch between a maxillary nerveand an SPG, an otic ganglion, an afferent fiber going into the oticganglion, an efferent fiber going out of the otic ganglion, aninfraorbital nerve, a vidian nerve, a greater superficial petrosalnerve, and a lesser deep petrosal nerve; and

a control unit, configured to:

drive the one or more electrodes to apply electrical stimulation to thesite during at least a first period of time and a second period of timeafter the first period, each of the first and second periods of timehaving a duration of at least one minute, and

configure the stimulation to excite nervous tissue of the site duringthe first period at a first stimulation strength and during the secondperiod at a second stimulation strength less than the first stimulationstrength, wherein the first and second stimulation strengths aresufficient to induce an increase in cerebral blood flow (CBF) of thesubject.

In an embodiment, each of the first and second periods has a duration ofat least one hour, and the control unit is configured to drive the oneor more electrodes to apply the stimulation during the first and secondperiods each having the duration of at least one hour.

In an embodiment, the control unit is configured to set the first andsecond stimulation strengths to be insufficient to induce a significantincrease in permeability of a blood-brain barrier (BBB) of the subject.

For some applications, the control unit is configured to receive aninput of a point in time, and to determine the first and second timeperiods with respect to the point in time.

In an embodiment, the control unit is configured to apply thestimulation during a third period of time after the second period, andconfigure the stimulation to excite the nervous tissue during the thirdperiod at a third stimulation strength that is less than the secondstimulation strength.

In an embodiment, the site includes the SPG, and the electrodes areconfigured to be applied to the SPG. For some applications, theapparatus includes an elongated support element configured to be placedwithin a greater palatine canal of the subject, sized to extend from apalate of the subject to the SPG, and having a distal end, and theelectrodes are fixed to the support element in a vicinity of the distalend thereof.

There is still additionally provided, in accordance with an embodimentof the present invention, a method for treating a subject, including:

applying electrical stimulation to a site of the subject selected fromthe group consisting of: a sphenopalatine ganglion (SPG), a greaterpalatine nerve, a lesser palatine nerve, a sphenopalatine nerve, acommunicating branch between a maxillary nerve and an SPG, an oticganglion, an afferent fiber going into the otic ganglion, an efferentfiber going out of the otic ganglion, an infraorbital nerve, a vidiannerve, a greater superficial petrosal nerve, and a lesser deep petrosalnerve; and

configuring the stimulation to excite nervous tissue of the site at astrength sufficient to induce at least one neuroprotective occurrenceselected from the group consisting of: an increase in cerebral bloodflow (CBF) of the subject, and a release of one or more neuroprotectivesubstances, and insufficient to induce a significant increase inpermeability of a blood-brain barrier (BBB) of the subject.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for treating a subject, including:

applying electrical stimulation to a site of the subject during at leasta first period of time and a second period of time after the firstperiod, each of the first and second periods of time having a durationof at least one minute, the site selected from the group consisting of:a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesserpalatine nerve, a sphenopalatine nerve, a communicating branch between amaxillary nerve and an SPG, an otic ganglion, an afferent fiber goinginto the otic ganglion, an efferent fiber going out of the oticganglion, an infraorbital nerve, a vidian nerve, a greater superficialpetrosal nerve, and a lesser deep petrosal nerve; and

configuring the stimulation to excite nervous tissue of the site duringthe first period at a first stimulation strength and during the secondperiod at a second stimulation strength less than the first stimulationstrength, wherein the first and second stimulation strengths aresufficient to induce an increase in cerebral blood flow (CBF) of thesubject.

There is also provided, in accordance with an embodiment of the presentinvention, a method for treatment, including:

identifying that a subject has suffered from an adverse cerebrovascularevent;

responsively to the identifying, applying, beginning at least threehours after the event, electrical stimulation to a site of the subjectselected from the group consisting of: a sphenopalatine ganglion (SPG),a greater palatine nerve, a lesser palatine nerve, a sphenopalatinenerve, a communicating branch between a maxillary nerve and an SPG, anotic ganglion, an afferent fiber going into the otic ganglion, anefferent fiber going out of the otic ganglion, an infraorbital nerve, avidian nerve, a greater superficial petrosal nerve, and a lesser deeppetrosal nerve; and

configuring the stimulation to excite nervous tissue of the site at astrength sufficient to induce at least one neuroprotective occurrenceselected from the group consisting of: an increase in cerebral bloodflow (CBF) of the subject, and a release of one or more neuroprotectivesubstances.

For some applications, applying the stimulation includes applying thestimulation beginning at least six hours after the event, such as leastnine hours after the event, at least 12 hours after the event, or atleast 24 hours after the event.

For some applications, configuring the stimulation includes setting thestrength to be insufficient to induce a substantial increase inpermeability of a blood-brain barrier (BBB) of the subject.

In an embodiment, the event includes a stroke, e.g., an ischemic stroke,and applying the stimulation includes applying the stimulation beginningat least three hours after the stroke. Alternatively, for someapplications, the event includes an aneurysm or an arteriovenousmalformation, or an anoxic brain injury caused, for example, by neardrowning, kidney failure, heart failure, chemical exposure, myocardialinfarction, or electric shock.

For some applications, applying the stimulation includes applying thestimulation intermittently.

In an embodiment, applying the stimulation includes applying thestimulation during a plurality of stimulation periods which includes atleast first and last stimulation periods, wherein initiation of thefirst period is at least three hours after the event; and setting aninter-period interval between the initiation of the first stimulationperiod and initiation of the last stimulation period to be at least 24hours, and configuring the stimulation includes configuring thestimulation during the first and last stimulation periods to induce theat least one neuroprotective occurrence.

In an embodiment, the site includes the SPG, and applying thestimulation includes applying the stimulation to the SPG. For someapplications, applying the stimulation includes placing an elongatedsupport element within a greater palatine canal of the subject, sized toextend from a palate of the subject to the SPG, and having a distal end;and applying the stimulation from a vicinity of the distal end of thesupport element.

There is further provided, in accordance with an embodiment of thepresent invention, a method for treating a subject, including:

applying, for at least 15 minutes per day during a period of at leastone week, an electrical current to a site of the subject selected fromthe group consisting of: a sphenopalatine ganglion (SPG), a greaterpalatine nerve, a lesser palatine nerve, a sphenopalatine nerve, acommunicating branch between a maxillary nerve and an SPG, an oticganglion, an afferent fiber going into the otic ganglion, an efferentfiber going out of the otic ganglion, an infraorbital nerve, a vidiannerve, a greater superficial petrosal nerve, and a lesser deep petrosalnerve; and

configuring the current to excite nervous tissue of the site at astrength sufficient to induce at least one of: an increase in cerebralblood flow (CBF) of the subject, and a release of one or moreneuroprotective substances.

For some applications, configuring the current includes setting thestrength to be less than 40% of a strength that induces a maximumincrease in CBF in the subject that is achievable by applying thecurrent. Alternatively or additionally, configuring the current includessetting the strength to a level that induces less than 40% of a maximumincrease in CBF in the subject that is achievable by applying thecurrent.

For some applications, applying the current includes applying thecurrent for less than 6 hours per day.

For some applications, applying the current includes implanting anelectrical stimulator in a vicinity of the site, and activating thestimulator to apply the current.

In an embodiment, configuring the current includes setting the strengthto be insufficient to induce a significant increase in permeability of ablood-brain barrier (BBB) of the subject. For some applications, settingthe strength includes setting the strength to be less than 40% of astrength that is sufficient to induce the significant increase inpermeability of the BBB.

In an embodiment, the site includes the SPG, and applying the currentincludes applying the current to the SPG. For some applications,applying the current includes: placing an elongated support elementwithin a greater palatine canal of the subject, sized to extend from apalate of the subject to the SPG, and having a distal end; and applyingthe current from a vicinity of the distal end of the support element.

For some applications, applying the current includes applying thecurrent for at least 30 minutes per day during the period of at leastone week, such as for at least 60 minutes per day during the period ofat least one week.

There is additionally provided, in accordance with an embodiment of thepresent invention, a method for treating a brain tumor of a subject,including:

administering a chemotherapeutic drug to the subject;

during a first period of time during which the drug is at a first levelin a systemic circulation of the subject, applying electricalstimulation to a site of the subject selected from the group consistingof: a sphenopalatine ganglion (SPG), a greater palatine nerve, a lesserpalatine nerve, a sphenopalatine nerve, a communicating branch between amaxillary nerve and an SPG, an otic ganglion, an afferent fiber goinginto the otic ganglion, an efferent fiber going out of the oticganglion, an infraorbital nerve, a vidian nerve, a greater superficialpetrosal nerve, and a lesser deep petrosal nerve, and configuring thestimulation to excite nervous tissue of the site at a first strengthsufficient to induce an increase in permeability of a blood-tumorbarrier (BTB) of the subject; and

during a second period of time during which the drug is at a secondlevel in the systemic circulation, the second level lower than the firstlevel, applying the stimulation to the site, and configuring thestimulation to excite the nervous tissue at a second strength that isgreater than the first strength.

In an embodiment, configuring the stimulation during the first periodincludes setting the first strength to be insufficient to induce asignificant increase in permeability of a blood-brain barrier (BBB) ofthe subject. Alternatively or additionally, configuring the stimulationduring the second period includes setting the second strength to besufficient to induce a significant increase in permeability of a BBB ofthe subject. Further alternatively or additionally, configuring thestimulation during the first and second periods includes setting thefirst strength to be insufficient to induce a significant increase inpermeability of a BBB of the subject, and the second strength to besufficient to induce the significant increase in the permeability of theBBB.

In an embodiment, the site includes the SPG, and applying thestimulation includes applying the stimulation to the SPG. For someapplications, applying the stimulation during the first and secondperiods includes: placing an elongated support element within a greaterpalatine canal of the subject, sized to extend from a palate of thesubject to the SPG, and having a distal end; and applying thestimulation from a vicinity of the distal end of the support element.

There is yet additionally provided, in accordance with an embodiment ofthe present invention, a method for treating a brain tumor of a subject,including:

administering a chemotherapeutic drug to the subject;

applying electrical stimulation to a site of the subject selected fromthe group consisting of: a sphenopalatine ganglion (SPG), a greaterpalatine nerve, a lesser palatine nerve, a sphenopalatine nerve, acommunicating branch between a maxillary nerve and an SPG, an oticganglion, an afferent fiber going into the otic ganglion, an efferentfiber going out of the otic ganglion, an infraorbital nerve, a vidiannerve, a greater superficial petrosal nerve, and a lesser deep petrosalnerve; and

configuring the stimulation to excite nervous tissue of the site at astrength sufficient to induce an increase in permeability of ablood-tumor barrier (BTB) of the subject, but insufficient to induce asubstantial increase in permeability of a blood-brain barrier (BBB) ofthe subject.

In an embodiment, the site includes the SPG, and applying thestimulation includes applying the stimulation to the SPG. For someapplications, applying the stimulation includes: placing an elongatedsupport element within a greater palatine canal of the subject, sized toextend from a palate of the subject to the SPG, and having a distal end;and applying the stimulation from a vicinity of the distal end of thesupport element.

The present invention will be more fully understood from the followingdetailed description of the embodiments thereof, taken together with thedrawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic pictorial view of an electrical stimulation systemcomprising an implantable stimulator for stimulation of an MTS, inaccordance with an embodiment of the present invention;

FIG. 2 is a schematic pictorial view of another stimulator forstimulation of an MTS, in accordance with an embodiment of the presentinvention;

FIG. 3 is a graph illustrating electrical stimulation protocols, inaccordance with an embodiment of the present invention;

FIG. 4 is a graph showing a rehabilitation protocol for treating stroke,in accordance with an embodiment of the present invention;

FIG. 5 is a graph showing changes in cerebral blood flow (CBF) vs.baseline using three different SPG stimulation protocols, measured inaccordance with an embodiment of the present invention;

FIG. 6 is a graph showing the effect of SPG stimulation beginning threehours after permanent middle cerebral artery occlusion (pCMAO) in rats,measured in accordance with an embodiment of the present invention;

FIGS. 7 and 8 are graphs showing results of an in vivo experimentassessing the effect of SPG stimulation performed three hours followingstroke, measured in accordance with an embodiment of the presentinvention;

FIGS. 9A-C are graphs showing the results of in vivo experimentsassessing the effect of SPG stimulation performed three hours followingstroke, measured in accordance with respective embodiments of thepresent invention;

FIG. 10 is a graph showing results of an in vivo experiment assessingthe effect of rehabilitative SPG stimulation, measured in accordancewith an embodiment of the present invention;

FIGS. 11A-C are graphs showing results of an in vivo experimentassessing the effect of rehabilitative SPG stimulation, measured inaccordance with an embodiment of the present invention;

FIGS. 12A-H are graphs showing results of an in vivo experimentassessing the effect of long-term rehabilitative SPG stimulation,measured in accordance with an embodiment of the present invention; and

FIG. 13 is a graph showing a protocol for treating a brain tumor, inaccordance with an embodiment of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 is a schematic pictorial view of an electrical stimulation system10 comprising an implantable stimulator 12, for stimulation of a“modulation target site” (MTS), as defined hereinabove, such as asphenopalatine ganglion (SPG) 22, in accordance with an embodiment ofthe present invention. In FIG. 1, a human nasal cavity 20 is shown, andstimulator 12 is implanted between the hard palate and themucoperiosteum (not shown) of the roof of the mouth. Branches ofparasympathetic neurons coming from SPG 22 extend to the middle cerebraland anterior cerebral arteries (not shown). Typically, one or morerelatively short electrodes 26 extend from stimulator 12 to contact orto be in a vicinity of an MTS, such as SPG 22.

For some applications, stimulator 12 is implanted on top of the bonypalate, in the bottom of the nasal cavity. Alternatively oradditionally, the stimulator is implanted at the lower side of the bonypalate, at the top of the oral cavity. In this instance, one or moreflexible electrodes 26 originating in the stimulator are passed throughthe palatine bone or posterior to the soft palate, so as to be in aposition to stimulate the SPG or another MTS. Further alternatively oradditionally, the stimulator may be directly attached to the SPG and/orto another MTS.

For some applications, stimulator 12 is delivered to a desired pointwithin nasal cavity 20 by removably attaching stimulator 12 to thedistal end of a rigid or slightly flexible introducer rod (not shown)and inserting the rod into one of the patient's nasal passages until thestimulator is properly positioned. As appropriate, the placement processmay be facilitated by fluoroscopy, x-ray guidance, fine endoscopicsurgery (FES) techniques or by any other effective guidance method knownin the art, or by combinations of the aforementioned. Typically, skintemperature and/or cerebral blood flow (CBF) is measured concurrentlywith insertion. CBF may be measured with, for example, a laser Dopplerunit positioned at the patient's forehead or transcranial Dopplermeasurements. Verification of proper implantation of the electrodes ontothe appropriate neural structure may be performed by activating thedevice, and generally simultaneously monitoring CBF.

For some applications, stimulator 12 is implanted using techniquesdescribed in U.S. patent application Ser. No. 10/535,024, filed Dec. 27,2005, entitled, “Surgical tools and techniques for stimulation,” whichis assigned to the assignee of the present application and isincorporated herein by reference, and/or in the above-mentioned PCTPublication WO 04/043218. For some applications, techniques describedherein are performed in combination with apparatus and/or methods thatare described in U.S. patent application Ser. No. 11/349,020, filed Feb.7, 2006, entitled, “SPG stimulation via the greater palatine canal,”which is assigned to the assignee of the present application and isincorporated herein by reference.

FIG. 2 is a schematic illustration of a stimulator control unit 30positioned external to a patient's body, in accordance with anembodiment of the present invention. At least one flexible electrode 32typically extends from control unit 30, through a nostril 12 of thepatient, and to a position within the nasal cavity that is adjacent toSPG 22.

In an embodiment of the present invention, techniques described hereinare performed in conjunction with techniques described in US PatentApplication Publication 2004/0220644, which is assigned to the assigneeof the present application and is incorporated herein by reference. Forexample, the substantially rigid support element described therein maybe initially quickly inserted into the stimulation site for acutetreatment, and an implantable stimulator 12 may be subsequentlyimplanted for longer-term treatment.

It is to be understood that electrodes 26 (FIG. 1) and 32 (FIG. 2) mayeach comprise one or more electrodes, e.g., two electrodes, or an arrayof microelectrodes. For applications in which stimulator 12 comprises ametal housing that can function as an electrode, typically one electrode26 is used, operating in a monopolar mode. Regardless of the totalnumber of electrodes in use, typically only a single or a doubleelectrode extends to SPG 22. Other electrodes 26 or 32 or a metalhousing of stimulator 12 are typically temporarily or permanentlyimplanted in contact with other parts of nasal cavity 20.

Each of electrodes 26 and/or 32 typically comprises a suitableconductive material, for example, a physiologically-acceptable materialsuch as silver, iridium, platinum, a platinum iridium alloy, titanium,nitinol, or a nickel-chrome alloy. For some applications, one or more ofthe electrodes have lengths ranging from about 1 to 5 mm, and diametersranging from about 50 to 100 microns. Each electrode is typicallyinsulated with a physiologically-acceptable material such aspolyethylene, polyurethane, or a co-polymer of either of these. Theelectrodes are typically spiral in shape, for better contact, and mayhave a hook shaped distal end for hooking into or near the SPG.Alternatively or additionally, the electrodes may comprise simple wireelectrodes, spring-loaded “crocodile” electrodes, or adhesive probes, asappropriate.

Reference is made to FIG. 3, which is a graph 100 illustratingelectrical stimulation protocols, in accordance with an embodiment ofthe present invention. Excitatory stimulation of an MTS (e.g., the SPG)induces changes in CBF, induces the release of one or moreneuroprotective substances, such as neuromodulators (e.g., nitric oxide(NO) and/or vasoactive intestinal polypeptide (VIP)), and/or modulatespermeability of the blood-brain barrier (BBB). The inventors have foundthat excitatory stimulation of an MTS at least a minimum thresholdstrength increases CBF, and that the increase in CBF is related to thestrength of the stimulation. The inventors have also found that at asufficiently high strength, such stimulation modulates the permeabilityof the BBB, in addition to increasing CBF.

“Strength,” as used in the present application, including the claims,means a total charge applied to an MTS in a given time period, e.g., oneminute, one hour, or one day. Strength is increased or decreased bychanging one or more parameters of the applied stimulation, such as theamplitude, number of cycles in a given time period, frequency, pulsewidth, or duty cycle (e.g., ratio of “on” to “off” time within a givencycle), as described hereinbelow in greater detail.

The y-axis of graph 100 indicates the strength of the stimulation of anMTS. The strength of the stimulation is determined by the values of theparameters of the stimulation, such as voltage, current, frequency,cycles per time period, and duty cycle. Stimulation at least a minimumCBF-increasing strength 102 increases CBF. Stimulation at such astrength also typically induces the release of one or moreneuroprotective substances, such as NO and/or VIP. A maximumCBF-increasing strength 106 is the strength at which CBF is maximallyincreased, i.e., further increases in strength do not further increaseCBF. The BBB is opened, i.e., the permeability of the BBB to largermolecules or substances that do not cross the intact BBB issignificantly increased, by stimulation having a strength in a range 108between a minimum BBB-opening strength 110 and maximum BBB-openingstrength 112 (beyond which increased strength does not result inadditional opening of the BBB). Although minimum BBB-opening strength110 is shown in graph 100 as being greater than maximum CBF-increasingstrength 106, this is not necessarily the case.

In the present application, including the claims, stimulation of an MTSis considered capable of inducing a “significant” increase in thepermeability of the BBB if the stimulation is capable of inducing atleast one of the following:

(a) an increase in concentration of Evans blue (EB) in brain tissue of asubject, such as a rat, of at least 100% compared to a baselineconcentration measured in a control rat. To determine the increase,permanent middle cerebral artery occlusion (pMCAO) is induced in therat, such as using techniques described hereinbelow with reference toFIG. 6. Three hours after pMCAO, stimulation is applied to the MTS, anda bolus of EB 2% at 1 ml per kg body weight of the rat is administeredintravenously. The rat is sacrificed one hour after application of thestimulation and administration of the EB. To determine the baselineconcentration, pMCAO is induced in a control rat, three hours afterpMCAO an identical EB bolus is administered intravenously, but nostimulation is applied, and the control rat is sacrificed one hour afterthe administration of the EB; and

(b) a serum S100beta level of the subject (indicative of clearance ofthe protein from the brain into the systemic circulation), at ameasurement time 45 minutes after initiation of MTS stimulation, that isat least 30% greater than a serum S100beta level of the subject measuredat the beginning of the MTS stimulation.

Although the above are indications of the “significance” of an increasein permeability of the BBB, use of the apparatus and performance of themethods described and claimed herein typically do not include measuringany of these indications. In particular, indication (a) is generallyonly possible to measure in an animal model; if it were desired toconduct a human experiment, different techniques would likely be used,such as measuring the concentration in the brain of a radioactiveisotope that is normally excluded by the BBB.

For some applications, it is desirable to apply stimulation to an MTS,and configure the stimulation to have a strength that induces anincrease in permeability of the BBB that is even lower than a“significant” increase, as defined above. Such a “sub-significant”increase in permeability of the BBB is considered to occur if thestimulation is capable of inducing at least one of the following: (i) anincrease in concentration of EB, under the conditions defined inindication (a) above, of at least 20%, such as at least 30%, e.g., atleast 50%; and (ii) a serum S100beta level, under the conditions definedin indication (b) above, that is at least 10%, e.g., at least 20%,greater than the level of the subject measured at the beginning of theMTS stimulation.

For some applications, it is useful to define increased CBF as apercentage increase in CBF over a baseline level of CBF, which increasehas at least a certain duration, e.g., at least 5 minutes. Typically,the baseline CBF level is either: (a) a normal baseline level for asubject, i.e., prior to an adverse brain event, such as acerebrovascular event, e.g., a stroke, or (b) a post-event baselinelevel, prior to stimulation using the techniques described herein, and,optionally, prior to other treatment of the event. CBF is typicallyexpressed as volume of blood flow per time per mass of the subject,e.g., ml/min/100 g. For some applications, increased CBF is expressed asan area under the curve (AUC) of CBF with respect to baseline over acertain time interval.

In an embodiment of the present invention, electrical stimulation system10 is configured to apply excitatory electrical stimulation to at leastone MTS of a subject, and to configure the stimulation to increase CBFof the subject and/or induce the release of neuroprotective substances,without substantially opening the BBB of the subject. In other words,the system sets the strength of stimulation equal to less than minimumBBB-opening strength 110, such as less than 90% of minimum BBB-openingstrength 110, e.g., less than 80%, 70%, or 60% of minimum BBB-openingstrength 110. For some applications, the system is configured toincrease CBF of the subject and/or induce the release of neuroprotectivesubstances without increasing the permeability of the BBB to a levelthat produces a measurably-harmful clinical effect for the subject.

For some applications, system 10 sets an acute strength 122 equal to alevel appropriate for treatment of an acute condition, such as anadverse brain event (e.g., a cerebrovascular event), for which increasedCBF and/or release of neuroprotective substances is beneficial, but forwhich opening the BBB is not indicated. For example, the system may setacute strength 122 equal to at least about 20% of minimum BBB-openingstrength 110, e.g., at least about 50%, 60%, 70%, or 80% of minimumBBB-opening strength 110.

In an embodiment of the present invention, system 10 is used forrehabilitative treatment after an adverse brain event, such as acerebrovascular event, e.g., a stroke, or for rehabilitative treatmentof a non-acute cerebrovascular condition. Such rehabilitativestimulation induces the release of neuroprotective substances and/ormaintains a slightly elevated level of blood flow, typically over anextended period of time, such as at least 24 hours, at least one week,at least two weeks, at least four weeks, or at least three months. As aresult, such stimulation typically rehabilitates damaged tissue,improves perfusion of the rehabilitating brain, and/or acceleratesangiogenesis. (See, for example, the above-mentioned article by Zhang Ret al. (2001), which reports that NO donors administrated 24 hours afterstroke significantly increased angiogenesis in the ischemic boundaryregions.) For some applications, the system is configured to apply suchrehabilitative stimulation intermittently, such as during one sessionper day, having a duration of between 1 minute and 6 hours, such as atleast 5 minutes or at least 15 minutes, or between 2 and 4 hours, e.g.,about 3 hours or about 6 hours, or more than 6 hours. Alternatively, thesystem is configured to apply such stimulation generally constantly,i.e., 24 hours per day. Further alternatively, the rehabilitativestimulation is applied less frequently than every day, such as onceevery other day (e.g., at least one minute during every 48 hours), ormore frequently than once per day, such as during two sessions per day.For some applications, such stimulation is applied beginning at leastone hour after the adverse brain event, such as a cerebrovascular event,e.g., a stroke, such as beginning at least 3 hours, at least 6 hours, atleast 9 hours, at least 12 hours, at least 24 hours, or at least 48hours after the brain event. For some applications, NO released bystimulation at rehabilitation strength 122 is of particularneuroprotective benefit during rehabilitation.

For some applications, such rehabilitative stimulation is applied duringa plurality of stimulation periods which includes at least first andlast stimulation periods. System 10 sets an inter-period intervalbetween initiation of the first period and initiation of the last periodto be at least 24 hours. For example, the first stimulation period mayoccur from 1:00 P.M. to 4:00 P.M. on a Monday, and the last stimulationperiod may occur from 1:00 P.M. to 4:00 P.M. on a Tuesday of the sameweek. Optionally, stimulation is applied during at least one additionalstimulation period between the first and last periods. For example,stimulation may be additionally applied from 1:00 A.M. to 4:00 A.M. onthe Tuesday. For some applications, the first period concludessimultaneously with the initiation of the last period, i.e., thestimulation is applied constantly from the beginning of the first perioduntil the conclusion of the last period. For example, the stimulationmay be applied constantly from 1:00 P.M. on Monday, January 1 to 4:00P.M. on Tuesday, January 2, or constantly from 1:00 P.M. on Monday,January 1 to 4:00 P.M. on Monday, January 29. Alternatively, theinitiation of the last stimulation period occurs after a conclusion ofthe first stimulation period, such that the stimulation is not appliedduring at least one non-stimulation period between the conclusion of thefirst stimulation period and the initiation of the last stimulationperiod.

For some applications, the system sets the inter-period interval to beat least 48 hours, such as at least one week, at least two weeks, or atleast four weeks. When using such greater inter-period intervals, thesystem typically, but not necessarily, applies stimulation during atleast several additional stimulation periods between the first and laststimulation periods. For some applications, such additional stimulationperiods may include a plurality of daily stimulation periods, applied onevery day between the initiation of the first stimulation period and theinitiation of the last stimulation period. For example, the firststimulation period may occur from 1:00 P.M. to 4:00 P.M. on Monday,January 1, the last stimulation period may occur from 1:00 P.M. to 4:00P.M. on Monday, January 8, and the additional daily stimulation periodsmay occur from 1:00 P.M. to 4:00 P.M. on each day from Tuesday, January2 through Sunday, January 7, inclusive. For some applications,stimulation is applied for at least 30 minutes every day (e.g., at least60 minutes every day) between the initiation of the first stimulationperiod and the initiation of the last stimulation period. For someapplications, stimulation is applied during a plurality ofnon-continuous stimulation periods during each 24-hour period betweenthe initiation of the first stimulation period and the initiation of thelast stimulation period. For example, the first stimulation period mayoccur from 1:00 P.M. to 4:00 P.M. on Monday, the last stimulation periodmay occur from 1:00 P.M. to 4:00 P.M. on Wednesday, and stimulation maybe applied during additional stimulation periods from (a) 1:00 A.M. to4:00 A.M. on Tuesday, (b) from 1:00 P.M. to 4:00 P.M. on Tuesday, and(c) from 1:00 A.M. to 4:00 A.M. on Wednesday, such that stimulation isapplied during two stimulation periods during the 24-hour period from1:00 P.M. on Monday to 1:00 P.M. on Tuesday, and during two stimulationperiods during the 24-hour period from 1:00 P.M. on Tuesday to 1:00 P.M.on Wednesday.

For some applications, the system is configured to set the inter-periodinterval to be no more than a maximum value, such as three, six, nine,or twelve months. For some applications, the system comprises a userinterface, which enables a healthcare worker to enter a value for theinter-period interval. The system typically rejects values that aregreater than the maximum value, such as by requiring the healthcareworker to enter another value, or by using the maximum value instead ofthe entered value. Alternatively, the system notifies the healthcareworker if the entered value is greater than the maximum value;optionally, the system allows the healthcare worker to override thenotification.

For some applications, the system is configured to store a maximum totaltime of stimulation per each time period having a given duration, and toapply the stimulation no more than the maximum total time per each timeperiod having the given duration. For example, the given duration ofeach time period may be 24 hours. Typical values for the maximum totaltime of stimulation per 24-hour period include one hour, three hours,six hours, ten hours, and twelve hours. For some applications, themaximum total time of stimulation is predetermined, e.g., by themanufacturer of the system, while for other applications, a healthcareworker enters the maximum total time of stimulation into the system.

As used in the present application, including the claims, a “stimulationperiod” includes an entire period during which stimulation is applied,even though current is applied to the site only during a portion of theperiod, because of the duty cycle, on/off periods, and/or frequency ofthe current, for example.

For some applications, system 10 sets the strength of stimulation duringsuch long-term rehabilitation to a rehabilitation strength 120, such asbetween about 10% and about 40% of minimum BBB-opening strength 110,e.g., between about 20% and about 30% of minimum BBB-opening strength110, or such as between about 10% and about 40% of maximumCBF-increasing strength 106, e.g., between about 20% and about 30% ofmaximum CBF-increasing strength 106. Alternatively or additionally,system 10 sets rehabilitation strength 120 to a level that causes anincrease in CBF equal to less than about 40% of a maximum CBF increasethat system 10 is capable of inducing.

In an embodiment of the present invention, system 10 sets the strengthof stimulation to a preventive strength appropriate for preventing anoccurrence of a brain event, typically a secondary brain event, e.g., asecondary stroke. For example, such strength may be between about 5% andabout 50% of the minimum BBB-opening strength 110. For someapplications, NO released by stimulation at the preventive strength isof particular neuroprotective benefit during prevention, and has ananti-thrombolytic, vasodilatory, and/or anti-inflammatory effect.

In an embodiment of the present invention, system 10 is configured totreat a complication of subarachnoid hemorrhage (SAH), such as acerebral vasospasm. The currently-preferred conventional treatment forSAH includes a surgical procedure in which a medical vehicle is used totreat the SAH. The medical vehicle may comprise, for example: (a) a toolfor treating the SAH such as by clipping the aneurysm that caused theSAH, and/or (b) a pharmaceutical treatment. However, the presence ofblood in the subarachnoid space sometimes causes increased sensitizationof large cerebral arteries, resulting at a later time in cerebralvasospasms. These late-onset vasospasms, in turn, cause brain ischemiaand often irreversible damage (see the above-mentioned article by VanGijn J et al.). Therefore, the stimulation of the MTS of this embodimentof the present invention is typically applied in conjunction with such atreatment (e.g., before, during or after the treatment), typically tothe SPG, in order to counteract the reduced CBF sometimes caused byblood passage into the subarachnoid space.

Typically, for treating the complication of SAH, system 10 configuresthe stimulation to increase CBF of the subject and/or induce the releaseof neuroprotective substances, without substantially opening the BBB ofthe subject. Typically, system 10 is configured to set the strength ofstimulation to at least acute strength 122, but no more than maximumCBF-increasing strength 106, so as not to substantially open the BBB.For some applications, the stimulation of the MTS is initiated at a timeafter the treatment when the hemorrhage has already been substantiallyreduced (at which time, in the absence of MTS stimulation, CBF isfrequently reduced below desired levels). Alternatively, the stimulationof the MTS is initiated prior to this point, but generally has itsstrongest elevating effect on CBF once the hemorrhage has beensubstantially reduced.

Reference is again made to FIG. 3. In an embodiment of the presentinvention, electrical stimulation system 10 is configured to applystaged treatment of a brain event, such as an ischemic event (e.g., astroke). The system configures the stimulation to dilate cerebralvessels, thereby increasing CBF to affected brain tissue and tissue in avicinity thereof, and/or to induce the release of one or moreneuroprotective substances, such as neuromodulators (e.g., nitric oxide(NO) and/or vasoactive intestinal polypeptide (VIP)). Such increased CBFand/or release of neuroprotective substances decrease damage caused bythe brain event. The system is typically configured to adjust at leastone parameter of the applied stimulation responsively to an amount oftime that has elapsed since the occurrence of the brain event. For someapplications, system 10 calculates the elapsed time responsively to anestimated time of occurrence of the brain event, which is entered intothe system by a healthcare worker, typically early in the treatment ofthe event. In these applications, the system typically automaticallyprogresses from stage to stage based on the elapsed time from theoccurrence of the event. Alternatively, for some applications, ahealthcare worker manually selects the stages.

System 10 is typically configured to apply the stimulation in two ormore stages. For some applications, during a first, acute stage 130, thesystem sets the parameters of stimulation to acute strength 122, whichis sufficient to cause a high level of cerebral vessel dilation and/or arelease of neuroprotective substances, but insufficient to substantiallyopen the BBB. Such stimulation is primarily intended to arrest thespreading of the initial ischemic core, such as by restoring blood flowto the penumbra in order to prevent damage to cells therein, and/or byreleasing neuroprotective substances, such as NO and/or VIP. Suchstimulation may also save some cells within the ischemic core, such asneuronal cells. The first stage of stimulation is typically appropriateduring the period beginning at the time of the event, and ending atabout 4 to 8 hours after the time of the event, such as at about 6 hoursafter the event. Alternatively, the first stage of stimulation isappropriate until about 24 hours after the time of the event. (See, forexample, the above-cited articles by Davis S M et al. and Phan T G etal.) For some applications, VIP released by stimulation at acutestrength 122 is of particular neuroprotective benefit. For someapplications, hypoperfused areas of the brain are identified, such as byusing MRI or PET, which can potentially be saved using the stimulationtechniques described herein.

During a second, rehabilitative stage 136, system 10 reduces thestrength of the stimulation to rehabilitation strength 120, andtypically applies the stimulation intermittently, such as during onesession per day, having a duration of between 1 minute and 6 hours, suchas between 2 and 4 hours, e.g., about 3 hours, or more than 6 hours.This rehabilitative level of stimulation continues to induce the releaseof neuroprotective substances, and/or maintains a slightly elevatedlevel of blood flow. This stage of stimulation is typically appliedduring the period beginning at the conclusion of acute stage 130, andlasting at least one week, such as at least two weeks, at least onemonth, at least three months, or at least six months. Alternatively, therehabilitative stimulation is applied generally constantly, i.e., 24hours per day. Further alternatively, the rehabilitative stimulation isapplied less frequently than every day, such as once every other day, ormore frequently than once per day, such during two sessions per day.

For some applications, system 10 is configured to apply stimulationduring an additional, post-acute stage 132, between acute stage 130 andrehabilitative stage 136. During post-acute stage 132, the systemreduces the strength of the stimulation to a post-acute strength 134,between acute strength 122 and rehabilitation strength 120. Thispost-acute strength is sufficient to maintain an increased level ofblood flow to and/or release of neuroprotective substances to theischemic core and the penumbra. The lower strength is less likely tocause potential side effects, such as aneurysm, that might occur if thesystem maintained the higher level of stimulation of the first stage.Typically, post-acute strength 134 is equal to between about 20% and 70%of minimum BBB-opening strength 110, such as between about 40% and 60%.Post-acute stage 132 typically begins at the conclusion of acute stage130, and ends at about 16 to 30 hours after the time of the event, suchas about 24 hours after the event.

The following table shows exemplary parameter ranges for some of thestimulation strengths and treatment protocols described hereinabove.

TABLE 1 Pulse No. of Signal width Cycles per Cycle on/off Indicationamplitude Hz (μsec) hour time (sec) Acute treatment 0.5-10 mA 10-30100-500 1-10 60/12, 4/15, Rehabilitation 0.5-10 mA 10-30 30/60Prevention of 0.5-10 mA 10-30 recurrence Minimum BTB  1-3.5 V 10-30100-500 1-100 45/45, Minimum BBB   1-4 V 10-30 45/90, Maximum BBB  3.5-8V 10-50 90/60, 4/15, 2/8

As indicated in Table 1, for some applications system 10 providesstimulation by applying a plurality of cycles of stimulation, each cycleincluding an “on” period (e.g., between 2 and 90 seconds) followed by an“off” period (e.g., between 8 and 90 seconds). Such cycles are applied acertain number of times per hour, typically spaced evenly throughout thehour. For example, if the cycles are applied four times per hour, thefour cycles may be applied at the beginning of the hour, 15 minutes intothe hour, 30 minutes into the hour, and 45 minutes into the hour,respectively. For some applications, each stimulation is applied in setsof two or more cycles. For example, if the stimulation is applied fourtimes per hour, a set of two cycles may be applied at the beginning ofthe hour, 15 minutes into the hour, 30 minutes into the hour, and 45minutes into the hour, respectively.

For some applications, in order to apply different strengths for thedifferent brain event protocols (acute treatment, post-acute treatment,rehabilitation, and prevention of recurrence of the event), system 10changes the amplitude of the applied signal and/or the number of cyclesper hour. Alternatively or additionally, the system changes thefrequency, pulse width, duration of the “on” periods, duration of the“off” periods, ratio of duration of the “on” to the “off” periods,number of cycles per set of cycles, or at least one other parameter ofthe stimulation.

Nitric oxide (NO) influences infarct size after focal cerebral ischemiaand also regulates neurogenesis in the adult brain. These observationssuggest that therapeutic approaches to stroke that target NO signalingmay provide neuroprotection and also enhance brain repair through cellreplacement (see Zhang R et al. (2001) and Sun Y et al., citedhereinabove). Utilizing a rat model, Zhang R et al. (2001) demonstratedthat treatment of stroke with nitric oxide (NO) donors reducesfunctional neurological deficits. Zhang F et al. (cited hereinabove)demonstrated that NO donors increase CBF to the ischemic territory andreduce the tissue damage resulting from focal ischemia. The protectiveeffect may result from an increase in CBF to the ischemic territory,probably the ischemic penumbra. NO and VIP have been found to be potentneuroprotectants in cell culture models (see the above-mentioned articleby Sandgren K et al.). Khan M et al. (cited hereinabove), usingS-nitrosothiols, a nitric oxide (NO) donor, demonstrated thatadministration of NO provided neuroprotection in a rat model of focalcerebral ischemia. Ziche M et al. (cited hereinabove) discuss the roleof NO, as a factor responsible for vasodilation, in physiological andpathological angiogenesis. The inventors hypothesize that the release ofNO induced by the stimulation techniques described herein may havetherapeutic benefits, even if such stimulation is applied beginningseveral hours, or even several days, after the stroke.

In an embodiment of the present invention, stimulation during acutestage 130 and/or post-acute stage 132 is performed using a needle-likeelectrode, which is inserted, using a simple procedure, into a subjectrecently admitted to a hospital after a stroke. For example, the devicedescribed with reference to FIGS. 1-4B and/or FIGS. 17A-C of theabove-mentioned U.S. patent application Ser. No. 11/349,020 may be usedfor the acute and/or post-acute stages. Upon completion of one or bothof these stages, and/or stabilization of the subject, the needle-likeelectrode is removed, and a longer-term stimulator is implanted and usedfor rehabilitative stage 136 and/or the preventive stage. For example,the device described with reference to FIGS. 5A-D, 12-14B, and/or 17A-Cof the '020 application may be used for the rehabilitative and/orpreventive stages.

Reference is made to FIG. 4, which is a graph 150 showing arehabilitation protocol for treating stroke, in accordance with anembodiment of the present invention. In accordance with this protocol,system 10 is configured to alternatingly apply stimulation at a first,rehabilitative level of strength, and at a second BBB-opening level ofstrength in conjunction with administration of a drug for rehabilitationfrom stroke. For example, the drug may include a growth factor, such asBDNF, GDNF, or NGF. Typically, the first rehabilitative level isrehabilitation strength 120, described hereinabove with reference toFIG. 3, and the second BBB-opening level falls within BBB-opening range108, such as maximum BBB-opening strength 112, described hereinabovewith reference to FIG. 3. System 10 is typically configured to apply therehabilitative stimulation intermittently, such as during one sessionper day, having a duration of between about 1 and about 6 hours, such asbetween about 2 and about 4 hours day, e.g., about 3 hours.Alternatively, the rehabilitative stimulation is applied less frequentlythan every day, such as once every other day, or more frequently thanonce per day, such as during two sessions per day.

System 10 is typically configured to apply the BBB-opening stimulationintermittently, such as for between about 0.5 and about 1 hour per day,or for between about 3 and about 6 hours per day, e.g., about 4 hoursper day. Alternatively, the BBB-opening stimulation is applied lessfrequently than every day, such as once every other day, or morefrequently than once per day, such as twice per day, or 24 times perday. The drug administered in conjunction with applying the BBB-openingstimulation is typically administered systematically, before and/orduring application of the BBB-opening stimulation. For someapplications, the rehabilitative stimulation is applied immediatelybefore or after the BBB-opening stimulation (as shown in FIG. 4), whilefor other applications the rehabilitative and BBB-opening stimulationsare applied non-contiguously (not shown in FIG. 4).

Reference is made to FIG. 5, which is a graph showing changes in CBF vs.baseline using three different SPG stimulation protocols, measured inaccordance with an embodiment of the present invention. 16 naïve ratswere anesthetized with a ketamine-xylazine combination, and a plasticholder was affixed to the skull for CBF measurement. A bipolar electrodewas brought into contact with the SPG and connected to a controller. TheSPG was stimulated for five minutes beginning after CBF stabilization,using the following signal parameters: 3.5 volts, 10 Hz, and a 500 μsecpulse width. The rats were divided into four groups, one of which servedas a control, and the other three received stimulation having differentduty cycles: 4 seconds on/15 seconds off, 60 seconds on/12 seconds off,and 90 second on/60 second off. As can be seen in FIG. 5 and in Table 2below, CBF significantly increased in two of the stimulation groups(4/15 and 60/12) vs. CBF baseline. The maximum increase in CBF vs.baseline (193%) was observed in the 60/12 stimulation group after twominutes of SPG stimulation. CBF in this group remained elevated even10-15 minutes after termination of SPG stimulation. The minimum increasein CBF vs. baseline (141%) was observed in the 90/60 stimulation group.It is clear from these results that SPG stimulation at the describedparameters significantly increases CBF, and that such increase wasstable at 10 minutes following SPG stimulation.

TABLE 2 CBF at 2 minutes [% change Group from baseline]  4/15 (n = 5)157 60/12 (n = 6) 193 90/60 (n = 5) 141

Reference is made to FIGS. 6-11C, which are graphs showing in vivoexperimental results, measured in accordance with respective embodimentsof the present invention. These animal experiments were performed totest the efficacy of the SPG stimulation techniques describedhereinabove for treating stroke. The experiments described withreference to FIGS. 6-11C used a rat middle cerebral artery occlusion(MCAO) model of stroke. As described in detail hereinbelow, theseexperiments demonstrated that:

-   -   SPG stimulation starting three hours following MCAO occlusion        significantly improved cerebral blood flow (CBF), decreased        infract size, and improved neuromuscular function;    -   SPG stimulation reduced mortality;    -   SPG stimulation for one or three hours per day for three days,        beginning 24 hours after MCAO, improved neuromuscular functions        for nine days following the insult; and    -   SPG stimulation for six hours per day for six days, beginning 24        hours after MCAO improved neuromuscular function at 13 and 28        days following occlusion.

Reference is made to FIG. 6, which is a graph showing the effect of SPGstimulation beginning three hours after permanent MCAO (pCMAO) in malerats, measured in accordance with an embodiment of the presentinvention. The graph shows changes in CBF vs. baseline, in anexperimental group (n=12) and in a control group (n=12). The SpragueDawley® (SD) rats were anesthetized with a ketamine-xylazine combination(85 mg/kg and 5 mg/kg respectively), and pMCAO was performed as follows.The right common carotid artery (CCA) was exposed through a midline neckincision and carefully dissected free from surrounding nerves andfascia, from its bifurcation to the base of the skull. The occipitalartery branches of the external carotid artery (ECA) were then isolated,and these branches were dissected and coagulated. The ECA was dissectedfurther distally and coagulated together with the terminal lingual andmaxillary artery branches, which was then divided. The internal carotidartery (ICA) was isolated and carefully separated from the adjacentvagus nerve, and the pterygopalatine artery was ligated close to itsorigin with a 5-0 nylon suture. A 4-0 silk suture was tied looselyaround the mobilized ECA stump, and a 4 cm length of 4-0 monofilamentnylon suture (the tip of the suture was blunted by using a flame, andthe suture was coated with silicone, prior to insertion) was insertedthrough the proximal ECA into the ICA, and from there into the circle ofWillis, effectively occluding the MCA. The surgical wound was closed andthe rats were returned to their cages to recover from anesthesia. Thesetechniques for performing pMCAO are similar to those described in theabove-mentioned article by Schmid-Elsaesser R et al.

SPG stimulation was initiated at three hours following pMCAO. Thestimulation regime included a duty cycle of 60 seconds on/12 secondsoff, at 2 mA and 10 Hz, with a 500 μsec pulse width. The stimulation wasapplied for five minutes every 30 minutes, for a period of 10 hours. Ascan be seen in FIG. 6, SPG stimulation markedly and significantlyincreased CBF levels in rats after pMCAO. The greatest increase wasobserved at 6 hours following MCAO.

FIGS. 7 and 8 are graphs showing results of an in vivo experimentassessing the effect of SPG stimulation performed three hours followingstroke, measured in accordance with an embodiment of the presentinvention. A rat pMCAO model of stroke was used to evaluate theneuroprotective benefits of SPG stimulation following stroke usingtechniques described herein. A three-hour delay prior to applyingstimulation was chosen to simulate the relatively late-stageintervention common in clinical settings. The results of this experimentdemonstrate that SPG stimulation provided significant neuroprotection.SPG stimulation reduced mortality, significantly improved neuromuscularfunction, and increased CBF.

32 SD rats were divided into an experimental group (n=15), and a controlgroup (n=17). pMCAO was performed using the techniques describedhereinabove. A bipolar electrode was brought into contact with the SPGipsilateral to the pMCAO, and connected to a controller. Three hoursafter pMCAO and prior to commencement of stimulation, all of the ratswere subjected to the first of three neuroscoring (behavioral) tests.Additional neuroscoring was performed at 24 and 48 hours post-pMCAO. SPGstimulation was initiated at three hours following pMCAO occlusion. Thestimulation regime included a duty cycle of 60 seconds on/12 secondsoff, at 2 mA and 10 Hz, with a 500 μsec pulse width. The stimulation wasperformed for five minutes every 30 minutes, for a period of 10 hours.Forty-eight hours following pMCAO, the rats were sacrificed, and theirbrains were removed for triphenyltetrazolium chloride (TTC) staining.Infarct volume was quantified at each coronal level in the area of thecontralateral hemisphere and the ipsilateral spared hemisphere. Thevolume of the total infarct was measured. The infarct volume wasquantified by computerized morphometric analysis using an imagingprogram.

As can be seen in FIG. 7 and in Table 3 below, SPG stimulation increasedCBF levels in the experimental group vs. the control group. SPGstimulation also decreased the sub-cortical and cortical infarct volumein the experimental group vs. the control group, as measured atforty-eight hours following pMCAO, as can be seen in FIG. 8, which showsthe infarct volume as a percentage of the total volume of bothhemispheres, and in Table 3. Mortality was lower in the experimentalgroup than in the control group, and neuroscore was higher in theexperimental group than in the control group, as is shown in Table 3.

TABLE 3 CBF (at 6 hours after MCAO) Infarct volume Neuroscore [ml/min/Mortality (at 48 hours) (at 24 hours) Group 100 g] [%] [%] [arbitraryunits] Control 99.3 47.1 38.3 3.3 Experimental 141.7 26.7 25.3 3.6

FIGS. 9A-C are graphs showing the results of in vivo experimentsassessing the effect of SPG stimulation performed three hours followingstroke, measured in accordance with respective embodiments of thepresent invention. A rat pMCAO model of stroke was used to evaluate theneuroprotective benefits of SPG stimulation following stroke usingtechniques described herein. Other than as described below, theseexperiments were conducted in the same manner as those describedhereinabove with respect to FIGS. 7 and 8 and Table 3. 24 SD rats weredivided into an experimental group (n=17), and a control group (n=12).

As can be seen in FIG. 9A, SPG stimulation increased CBF levels in theexperimental group vs. the control group. SPG stimulation also decreasedthe sub-cortical and cortical infarct volume in the experimental groupvs. the control group, as measured at forty-eight hours following pMCAO,as can be seen in FIG. 9B, which shows the infarct volume as apercentage of the total volume of both hemispheres. Neuroscore wasslightly lower in the experimental group than in the control group at 3hours after pMCAO, but was significantly (P<0.05) higher in theexperimental group at 24 hours after pMCAO, as shown in FIG. 9C(neuroscore was assessed on a scale of 0 to 12, with 12 representing thebest performance).

Reference is made to FIG. 10, which is a graph showing results of an invivo experiment assessing the effect of rehabilitative SPG stimulation,measured in accordance with an embodiment of the present invention. Arat MCAO (middle cerebral artery occlusion) model of stroke was used toevaluate the neuromuscular benefits of rehabilitative SPG stimulationusing the techniques described herein. 47 rats were divided into threegroups: a control group (n=18); a first experimental group (n=16), whichreceived one hour of SPG stimulation per day; and a second experimentalgroup (n=13), which received three hours of SPG stimulation per day.pMCAO was performed using the techniques described hereinabove withreference to FIG. 6. A bipolar electrode was brought into contact withthe SPG ipsilateral to the pMCAO, and connected to a controller. SPGstimulation was initiated at 24 hours after pMCAO, in order todemonstrate the potential rehabilitative effects of such stimulation,rather than the acute benefits. The first and second experimental groupseach received SPG stimulation at 24 hours, 48 hours, and 72 hours afterpMCAO. The stimulation regime included a duty cycle of 60 seconds on/12seconds off, at 2 mA and 10 Hz, with a 500 sec pulse width. As mentionedabove, the stimulation was performed for one hour per day in the firstexperimental group, and three hours per day in the second experimentalgroup.

At 24, 48, 72, 96, and 216 hours after pMCAO, the rats were tested usinga modified neuroscore battery, which assessed the severity of damage ona scale of 0 to 10, with 10 representing the greatest deficit. As can beseen in FIG. 10, the rats in both the first and second experimentalgroups achieved better (lower) neuroscores than the control group at alltested time periods after pMCAO, with statistical significance achievedfor the second (3 hour stimulation) experimental group at nine daysafter pMCAO.

Reference is made to FIGS. 11A-C, which are graphs showing results of anin vivo experiment assessing the effect of rehabilitative SPGstimulation, measured in accordance with an embodiment of the presentinvention. A rat MCAO model of stroke was used to evaluate the benefits,including neuromuscular benefits, of rehabilitative SPG stimulationusing the techniques described herein. 29 rats were divided into anexperimental group (n=16) and a control group (n=13). Transient MCAO(tMCAO) was performed as follows. The right common carotid artery (CCA)was exposed through a midline neck incision and carefully dissected freefrom surrounding nerves and fascia, from its bifurcation to the base ofthe skull. The occipital artery branches of the external carotid artery(ECA) were isolated, and these branches were dissected and coagulated.The ECA was further dissected distally and coagulated together with theterminal lingual and maxillary artery branches, which were divided. Theinternal carotid artery (ICA) was isolated and carefully separated fromthe adjacent vagus nerve, and the pterygopalatine artery was ligatedclose to its origin with a 5-0 nylon suture. A 4-0 silk suture was tiedloosely around the mobilized ECA stump, and a 4 cm length of 4-0monofilament nylon suture (the tip of the suture was blunted using aflame, and the suture was coated with silicone, prior to insertion) wasinserted through the proximal ECA into the ICA, and from there into thecircle of Willis, effectively occluding the MCA. The suture was placedfor three hours and thereafter removed. The surgical wound was closed,and the animals were returned to their cages to recover from theprocedure. These techniques for performing tMCAO are similar to thosedescribed in the above-mentioned article by Schmid-Elsaesser R et al. Onthe day of the tMCAO procedure, a bipolar electrode was implanted incontact with the SPG ipsilateral to the tMCAO, and connected to acontroller.

At 24 hours after tMCAO, and prior to commencement of the firststimulation, neurological evaluation was performed on the rats using themodified Neurological Severity Score (mNSS) scale. Only animals with anoverall score of at least 12 were included in the experiment. The ratsin the experimental group received SPG stimulation for 6 hours per dayfor 6 days, beginning 24 hours after tMCAO. The stimulation regimeincluded a duty cycle of 60 seconds on/12 seconds off, at 2 mA and 10Hz, with a 500 μsec pulse width. Neuroscores were assessed at days 6,13, and 28 after tMCAO, using behavioral tests aimed at studyingneuromuscular function. FIGS. 11A and 11B show results obtained at days13 and 28, respectively (the mNSS scale ranges from 0 to 12, with bestperformance indicated by a 12). A significant improvement inneuromuscular function can be seen at both days 13 and 28. FIG. 11Cshows the results of a stepping test for the left and right paws. Asignificant improvement in motor function in the experimental groupcompared with the control group can be seen for the contralateral (left)paw.

Reference is made to FIGS. 12A-H, which are graphs showing results of anin vivo experiment assessing the effect of long-term rehabilitative SPGstimulation, measured in accordance with an embodiment of the presentinvention. A rat tMCAO model of stroke was used to evaluate thebenefits, including neuromuscular, motility, cognitive, somatosensory,somatomotor, infarct volume benefits, of rehabilitative SPG stimulationusing the techniques described herein. The stimulation was applied forseven consecutive days beginning at 24 hours after reperfusion in thetMCAO model.

94 male Sprague Dawley (SD) rats were divided into six groups, as shownin Table 4:

TABLE 4 Hours of stimulation Group No. of rats per day 1—Control 18 N/A2—Sham 10 N/A 3 17 1 4 16 3 5 17 6 6 16 10 

Prior to performance of any surgical procedure on the rats, the ratswere trained using a series of behavior tests. Five parameter categorieswere evaluated using one or more tests, as follows:

-   -   Neuromuscular function—rotarod motor test, mNSS test, beam        walking and balance test, stepping test, and staircase skilled        reaching test;    -   Motility—open field test;    -   Learning memory (cognitive)—water maze test;    -   Somatosensory sensation—adhesive removal test; and    -   Somatomotor sensation—corner turn test.

Transient MCAO (tMCAO) was performed on the right hemisphere of all ofrats except those of the sham group, using the techniques describedhereinabove with reference to FIGS. 11A-C. Three hours after theocclusion, reperfusion was allowed in all groups. On the day of tMCAO,the rats were anesthetized, and a bipolar electrode was implanted incontact with the SPG ipsilateral to the pMCAO (i.e., the right SPG), andconnected to a controller. At 24 hours post-tMCAO (just prior tostimulation), the rats were subjected to neuroscoring using the mNSSscale, which has a score range of 0-18, where 0 represents normal and 18represents maximum neurological defect. Rats scoring less than or equalto 9 were excluded from the experiment.

SPG stimulation was applied for seven consecutive days beginning at 24hours post-tMCAO, using the following regime: a duty cycle of 60 secondson/12 seconds off, with two cycles every 15 minutes, at 2 mA and 10 Hz,with a 500 μsec pulse width. The stimulation was applied for fifteenminutes every 60 minutes. The number of hours of stimulation per day wasas shown in Table 4 above.

In order to assess rehabilitation, on days 8, 14, and 35 post-tMCAO,(with limited exceptions for specific tests), the rats were subjected tothe same pre-procedure behavior tests used in the training, as describedhereinabove. One day after the last behavior testing, the rats weresacrificed and perfused. Their brains were harvested, infarct volume wasmeasured, and neurons were counted.

The results of the experiment included the following:

-   -   Mortality in the SPG-stimulated groups was lower than in the        non-stimulated control group.    -   SPG stimulation generally improved neuromuscular functions        (rotarod, mNSS, beam walk and balance, stepping and staircase        tests) in comparison to the non-stimulated control group,    -   SPG stimulation improved cognitive capabilities (water maze        test) in comparison to the non-stimulated control group.    -   There was a trend towards increased motility (open field test)        in the SPG-stimulated groups.    -   Somatosensory sensations were enhanced in the SPG-stimulated        groups in comparison to the non-stimulated control group.    -   Somatomotor competence was superior in the SPG-stimulated groups        than in the non-stimulated control groups.    -   SPG stimulation resulted in higher neurons counts in cortical        layer V of the ipsilateral stimulated side in comparison to the        non-stimulated control group.

In summary, in the present experiment, SPG stimulation initiated 24hours after tMCAO had advantageous results for all five parameter groupsevaluated. In addition, SPG stimulation increased the number of neuronsin all regions counted.

FIG. 12A is a graph showing neuroscores (mNSS test) of all six groups,measured at 24 hours, 8 days, 14 days, and 35 days after tMCAO, measuredin accordance with an embodiment of the present invention. As can beseen in the graph, mNSS scores of the SPG-stimulated rats decreased in atime-dependent manner post-tMCAO, indicating the occurrence of an activerestorative, rehabilitative process. SPG stimulation markedly andsignificantly (p<0.05) improved neurological function measured at days8, 14, and 35 in all SPG-stimulated groups.

FIG. 12B is a graph showing the results of the stepping test performedon the left foreleg in all six groups, measured pre-tMCAO and at 8 days,14 days, and 35 days after tMCAO, measured in accordance with anembodiment of the present invention. As can be seen in the graph, therewas a significant (p<0.05) increase in left (impaired) foreleg steppingin all SPG-stimulated rats in comparison to the non-stimulated controlgroup (with the exception of the 10-hour stimulated group at day 35).Maximum improvement was evident in the 3- and 6-hour stimulation groupsat days 14 and 35, respectively.

FIGS. 12C-F are graphs showing the results of the Morris water maze (WM)task, measured in accordance with an embodiment of the presentinvention. The Morris WM task is a standard test of learning in whichthe animal repeatedly searches for a rest platform hidden beneath thesurface in a pool. The test is especially sensitive to hippocampal andcortical damage, and reflects attention, memory, and learning strategy.The Morris WM task was performed on days 14 and 35 following tMCAO.

FIG. 12C is a graph showing the latency to the first occurrence in theOld Zone (as described below) in first and second trials at 14 daysafter tMCAO, measured in accordance with an embodiment of the presentinvention. This parameter assesses the rats' functional memory. The restplatform was moved from the Old Zone (its position during training) tothe New Zone (its position during testing), and the rats were expectedto seek the Old Zone. The first trial showed that the SPG-stimulatedrats (3-, 6-, and 10-hour stimulation) returned to the Old Zonesignificantly (p<0.05) more quickly than the non-stimulated rats in thecontrol group. The second trial showed, although non-significantly, thatthe SPG-stimulated rats returned to the Old Zone faster than thenon-stimulated controls, even though introduced to the New Zone restplatform in the first trial. The second trial thus confirmed that theSPG-stimulated rats showed enhanced remnants of functional memory.

FIG. 12D is a graph showing time spent in the Old Zone at day 14 aftertMCAO, measured in accordance with an embodiment of the presentinvention. This parameter also assesses the rats' functional memory. Ascan be seen in the graph, the 3-, 6-, and 10-hour SPG-stimulated groupsspent significantly (p<0.05) more time seeking the rest platform in theOld Zone in comparison to the non-stimulated control group.

FIG. 12E is a graph showing the latency to the first occurrence in theNew Zone in first and second trials at day 35 after tMCAO, measured inaccordance with an embodiment of the present invention. This parameteralso assessed the rats' functional memory. In the first trial, the 3-,6-, and 10-hour SPG-stimulated groups demonstrated superior, althoughnon-significant, results in finding the New Zone, compared with thenon-stimulated control group. In the second trial, all of theSPG-stimulated groups achieved better results than the non-stimulatedcontrol group. These results were significant (p<0.05) only in the3-hour stimulated group.

FIG. 12F is a graph showing the distance moved to find the rest platformin the New Zone in first and second trials at day 35 after tMCAO,measured in accordance with an embodiment of the present invention. Thisparameter assessed the rats' long-term learning capability. In bothtrials the SPG-stimulated rats demonstrated better performance than thecontrol group. These results were significant (p<0.05) only in the3-hour stimulated group during the first trial.

The staircase test (results not shown) was performed to assess therehabilitation of foreleg fine motorics. At day 14 after tMCAO theSPG-stimulated groups demonstrated better performance in the leftimpaired foreleg than the control group (1-, 3-, and 6-hour stimulation,significant (p<0.05) in the 3- and 6-hour stimulated rats only). At day35 after tMCAO the SPG-stimulated groups demonstrated better performancein the left impaired foreleg, significant (p<0.05) in the 3-hourstimulated rats only.

The rotarod test (results not shown) was performed to assess the rats'ability to remain on a rotating rod. It requires a high degree ofsensorimotor coordination and is sensitive to damage in the basalganglia and the cerebellum. The only significant (p<0.05) results werein the 3-hour stimulated rats on the 35 day assessment, which remainedon the rotarod significantly longer than the control group.

FIG. 12G is a graph showing the time required for the rats to remove anadhesive patch from the left foreleg, measured in accordance with anembodiment of the present invention. This test assessed both cutaneoussensitivity and sensor motor integration, and is analogous to humanneurological tests used clinically in stroke patients. In the leftimpaired foreleg, the SPG-stimulated rats showed better results than thenon-stimulated controls at all assessment days (8, 14, and 35 days).These results were significant (p<0.05) at all three assessment days inthe 3- and 6-hour stimulated groups only.

The corner test (results not shown) was performed to evaluate the rats'tendency to favor a turn in the direction of the ipsilateral side of thetMCAO (i.e., the right side in the experiment). On all three assessmentdays (8, 14, and 35 days), all SPG-stimulated groups showed a decreasein right side turns in comparison to the non-stimulated control group.This decrease was significant (p<0.05) only on day 35 in the 1- and6-hour stimulated rats.

The beam walk test (results not shown) was performed to evaluate sensormotor integration, specifically hind limb function. In general, allSPG-stimulated groups showed improved results in comparison to thenon-stimulated control group. These results were significant (p<0.05)only on day 35 only in the 3-hour stimulated group.

The beam balance test (results not shown) was performed to assess grossvestibulomotor function, by requiring the rats to balance steadily on anarrow beam. This test is sensitive to motor cortical insults. On allassessment days (days 8, 14, and 35), all of the SPG-stimulated groups(except the 1-hour stimulated group on day 8) performed better than thenon-stimulated control group. These results were significant (p<0.05)only on day 14 in the 3-hour stimulated group.

The open field test (results not shown) was performed to assess thefollowing four parameters indicative of hippocampal and basal gangliadamage, as well as hind limb dysfunction:

-   -   Total distance moved, which decreases in cerebrally-insulted        animals. All of the SPG-stimulated groups achieved enhanced        movement compared to the control group on day 14 after tMCAO.        These results were significant (p<0.05) only in the 3- and        6-hour stimulated groups.    -   Velocity, which is diminished in cerebrally-insulted animals.        All of the SPG-stimulated groups achieved enhanced velocity        compared to the control group on day 14 after tMCAO. These        results were significant (p<0.05) only in the 3- and 6-hour        stimulated groups.    -   Latency of first occurrence in center zone. All of        SPG-stimulated groups (except the 10-hour stimulated group on        day 14) showed quicker entry into the center zone in comparison        to the non-stimulated control group. These results were        significant (p<0.05) only on day 35 in the 1- and 3-hour        stimulated groups.    -   Total distance moved in center zone. On day 14, the 3- and        10-hour stimulated groups achieved significantly (p<0.05)        greater distance moved than the control group.

FIG. 12H is a graph showing the number of neurons in cortical layer Vand measured in accordance with an embodiment of the present invention.Neuron counting was performed in cortical layers V and II-III in thenon-stimulated control group and in the 3- and 6-hour SPG-stimulatedgroups. The number of neurons in cortical layer V was significantly(p<0.05) greater in both of these SPG-stimulated groups compared to thenon-stimulated group. In cortical layers II-III there was no significantdifference between the stimulated and non-stimulated groups.

There were no significant differences in body weigh between theSPG-stimulated groups and the non-stimulated control group.

The inventors are currently performing an in vivo experiment to comparethe application of SPG stimulation for 28 days with the application ofSPG stimulation for 7 days, as applied in the experiment describedhereinabove with reference to FIGS. 12A-H. The experimental protocol issimilar to that of this above-mentioned experiment. Preliminary resultsof this current experiment indicate that application of SPG stimulationfor the longer 28-day period has greater therapeutic benefits thanapplication of the stimulation for 7 days.

Table 5 shows the results of an in vivo experiment performed to testwhether long-term stimulation of the SPG using a protocol appropriatefor treating stroke damages the BBB, measured in accordance with anembodiment of the present invention. 31 rats (males, Wistar™, 12 weeks,average body weight 300 g) were divided to three groups: an SPGstimulation group (n=13), which had an SPG stimulator implanted; a firstcontrol group (n−12), which was not stimulated, and had a shamoperation; and a second control group (n=6), which had a sham operation,and was exposed to an RF electromagnetic field for 24 hours. The SPGstimulation group received 24 hours of continuous SPG stimulation with astimulation regime that included a duty cycle of 90 seconds on/60seconds off, at 5 V and 10 Hz, with a 1 millisecond pulse width. Uponcompletion of stimulation, a marker (Evans blue (EB) (2%)), whichnormally does not cross the BBB, was intravenously (2 ml) injected intothe rats. 48 hours following the EB administration, 500 ml of coldsaline was used for perfusion of blood and EB from the rats'circulation. Thereafter, the rats' brains were removed, the left andright hemispheres were homogenized, and brain EB concentration wasdetermined using an Elisa Reader at 630 nm. As can be seen in Table 5,stimulation for 24 hours did not cause leakage of EB into the brain,indicating that the stimulation did not cause damage to the BBB.

TABLE 5 Right Left Group Hemisphere Hemisphere First Control(non-stimulated) (n = 12) 0.04 ± 0.03 0.02 ± 0.02 Second Control(RF-exposed) (n = 6) 0.03 ± 0.02 0.04 ± 0.02 Experimental (stimulated)(n = 13) 0.03 ± 0.02 0.02 ± 0.02

The inventors performed in vivo experiments in rats to assess the safetyof SPG stimulation techniques described herein. These experiments showedthat stimulation did not break down the BBB, and that stimulation wasfound to be safe in a battery of motor and cognitive tests, which werein general agreement with histological analysis.

In an embodiment of the present invention, a calibration procedure isperformed, in which a test molecule is injected into the systemic bloodcirculation of the subject, and a threshold stimulation strength isdetermined by stimulating at least one MTS, and gradually increasing thestimulation strength until the BBB is opened (e.g., as determined usinga radioactive scanning technique). System 10 applies therapeuticstimulation to an MTS using a strength equal to a certain percentage ofthe threshold strength, typically less than 100%.

Reference is made to FIG. 13, which is a graph 160 showing a protocolfor treating a brain tumor, in accordance with an embodiment of thepresent invention. In accordance with this protocol, a method fortreating a brain tumor comprises: (a) during a first period of time 170,applying excitatory electrical stimulation to at least one MTS at afirst, relatively low strength 152, in conjunction with administrationof a chemotherapeutic drug at a first, relatively high dosage 174; and(b) during a second period of time 176, applying the stimulation at asecond strength 178 greater than first strength 152, in conjunction withadministration of the drug at a second dosage 180 lower than firstdosage 174. Alternatively, the drug is administered only at the firstdosage, and the stimulation is applied at second strength 178 after thelevel of the drug in the systemic circulation has dropped because ofordinary metabolic drug clearance from the circulation. For someapplications, the protocol shown for second period 176 is applied afterfirst period 170 (as shown). For other applications, the protocol shownfor the second period is applied before the protocol shown for the firstperiod. Alternatively, two different chemotherapeutic drugs are appliedduring the first and second periods, respectively, not necessarily atdifferent dosages.

The blood-tumor barrier (BTB) of the core and tissue near the core of agrowing brain tumor is generally damaged by the natural progression ofthe tumor. During first period 170, stimulation applied at firststrength 172 is thus sufficient to further open the BTB of the core andtissue near the core, but not sufficient to open the BBB of theperiphery of the tumor or of other cells in the brain. In other words,first strength 172 is between a BTB opening strength 173 and maximumBBB-opening strength 112. As a result, high dosage 174 of thechemotherapeutic drug is targeted at the core and tissue near the coreof the tumor, since the drug is substantially unable to enter otherbrain cells, because of their intact BBB and the large molecular size ofthe drug. During second period 176, stimulation at higher secondstrength 178 opens the BBB of other brain cells, including tumor cellsin the periphery of the core and/or other areas of the brain. For someapplications, second strength 178 is greater than or equal to maximumBBB-opening strength 112, as shown in FIG. 13. Alternatively oradditionally, second strength 178 is sufficient to induce a significantincrease in the permeability of the BBB. Second dosage 180 is low enoughnot to substantially damage non-tumor cells. For some applications, thedosage is set to the highest level that does not cause systemic and/orbrain toxicity; this level is higher during first period 170 than duringsecond period 176, because of the lower level of MTS stimulation duringthe first period than during the second period. For some applications,only the protocol for the first period is applied, when this is deemedsufficient to facilitate delivery of the drug to the core and tissuenear the core while generally avoiding facilitating delivery of the druginto other brain cells. For some applications, in order to determine theappropriate parameters for increasing the permeability of the BTB and/orBBB for this embodiment, a calibration procedure is performed in whichthe uptake of a substance across the BTB and/or BBB is measured at aplurality of stimulation parameters (e.g., using a radioactive isotopeor other marker known in the art).

In an embodiment of the present invention, bipolar stimulation isapplied, in which a first electrode is applied to a first MTS, and asecond electrode is applied to a second MTS.

In an embodiment of the present invention, an SPG of the subject isindirectly activated by stimulating a branch of cranial nerve V of thesubject, including, for example, afferent fibers of cranial nerve V,either electrically, magnetically, or electromagnetically. A reflexresponse to such stimulation leads to activation of the SPG. Typically,the stimulation is performed while the subject is under generalanesthesia or sedation. For some applications, cranial nerve V isstimulated by non-invasively attaching electrodes to the surface of theface of the subject, typically using techniques commonly used fortranscutaneous electrical nerve stimulation (TENS).

In an embodiment of the present invention, an SPG of the subject isindirectly activated by stimulating afferent fibers of the trigeminalnerve (cranial nerve V) of the subject, either electrically,magnetically, or electromagnetically. A reflex response to suchstimulation leads to activation of the SPG. (For example, the maxillarybranch of the trigeminal nerve directly contacts the SPG.) Typically,but not necessarily, such stimulation is performed while the subject isunder general anesthesia or sedation. For some applications, cranialnerve V is stimulated by non-invasively attaching electrodes to thesurface of the face of the subject, typically using techniques commonlyused for transcutaneous electrical nerve stimulation (TENS). Forexample, TENS may be applied to a cheek or a tip of a nose of a subject.In an embodiment of the present invention, an oral appliance is providedthat is configured to be brought into contact with a mucous membrane ofa palate of an oral cavity of a subject. The appliance comprises one ormore electrodes, which are driven to apply transmucosal electricalstimulation to nerve fibers within or immediately above the mucousmembrane, which fibers directly innervate an SPG of the subject.Typically, but not necessarily, such stimulation is performed while thesubject is under general anesthesia or sedation. Such transmucosalstimulation may require less current than the transcutaneous stimulationdescribed hereinabove.

In some embodiments of the present invention, techniques describedherein are practiced in combination with techniques described in one ormore of the references cited in the Background of the Invention sectionhereinabove and/or in combination with techniques described in one ormore of the patent applications cited hereinabove.

The scope of the present invention includes embodiments described in thefollowing patent applications, which are assigned to the assignee of thepresent patent application and are incorporated herein by reference. Inan embodiment of the present invention, techniques and apparatusdescribed in one or more of the following applications are combined withtechniques and apparatus described herein:

-   -   U.S. Provisional Patent Application 60/203,172, filed May 8,        2000, entitled, “Method and apparatus for stimulating the        sphenopalatine ganglion to modify properties of the BBB and        cerebral blood flow”    -   U.S. patent application Ser. No. 10/258,714, filed Oct. 25,        2002, which issued as U.S. Pat. No. 7,120,489, entitled, “Method        and apparatus for stimulating the sphenopalatine ganglion to        modify properties of the BBB and cerebral blood flow,” or the        above-referenced PCT Publication WO 01/85094    -   U.S. Provisional Patent Application 60/364,451, filed Mar. 15,        2002, entitled, “Applications of stimulating the sphenopalatine        ganglion (SPG)”    -   U.S. Provisional Patent Application 60/368,657, filed Mar. 28,        2002, entitled, “SPG Stimulation”    -   U.S. Provisional Patent Application 60/376,048, filed Apr. 25,        2002, entitled, “Methods and apparatus for modifying properties        of the BBB and cerebral circulation by using the neuroexcitatory        and/or neuroinhibitory effects of odorants on nerves in the        head”    -   U.S. Provisional Patent Application 60/388,931, filed Jun. 14,        2002, entitled “Methods and systems for management of        Alzheimer's disease,” PCT Patent Application PCT/IL03/000508,        filed Jun. 13, 2003, claiming priority therefrom, and which        published as PCT Publication WO 03/105658, and a US patent        application filed Dec. 14, 2004 in the national stage thereof,        which issued as U.S. Pat. No. 7,640,062    -   U.S. Provisional Patent Application 60/400,167, filed Jul. 31,        2002, entitled, “Delivering compounds to the brain by modifying        properties of the BBB and cerebral circulation”    -   U.S. Provisional Patent Application 60/426,180, filed Nov. 14,        2002, entitled, “Surgical tools and techniques for        sphenopalatine ganglion stimulation,” PCT Patent Application        PCT/IL03/000966, filed Nov. 13, 2003, which claims priority        therefrom, and which published as PCT Publication WO 04/043218,        and a U.S. patent application filed May 11, 2005 in the national        stage thereof, which issued as U.S. Pat. No. 7,636,597    -   U.S. Provisional Patent Application 60/426,182, filed Nov. 14,        2002, and corresponding PCT Patent Application PCT/IL03/000967,        which claims priority therefrom, filed Nov. 13, 2003, which        published as PCT Publication WO 04/044947, entitled,        “Stimulation circuitry and control of electronic medical        device,” and a U.S. patent application filed May 11, 2005 in the        national stage thereof    -   U.S. patent application Ser. No. 10/294,310, filed Nov. 14,        2002, which issued as U.S. Pat. No. 7,146,209, entitled, “SPG        stimulation for treating eye pathologies,” which published as        U.S. Patent Application Publication 2003/0176898, and PCT Patent        Application PCT/IL03/000965, filed Nov. 13, 2003, claiming        priority therefrom, which published as PCT Publication WO        04/043217    -   PCT Patent Application PCT/IL03/000631, filed Jul. 31, 2003,        which published as PCT

Publication WO 04/010923, entitled, “Delivering compounds to the brainby modifying properties of the BBB and cerebral circulation,” whichpublished as PCT Publication WO 04/010923, and U.S. patent applicationSer. No. 10/522,615 in the national stage thereof

-   -   U.S. Pat. No. 6,853,858 to Shalev    -   U.S. patent application Ser. No. 10/783,113, filed Feb. 20,        2004, entitled, “Stimulation for acute conditions,” which        published as US Patent Application Publication 2004/0220644    -   U.S. Provisional Patent Application 60/426,181, filed Nov. 14,        2002, entitled, “Stimulation for treating ear pathologies,” PCT        Patent Application PCT/IL03/000963, filed Nov. 13, 2003, which        claims priority therefrom, and which published as PCT        Publication WO 04/045242, and which published as PCT Publication        WO 04/045242, and U.S. patent application Ser. No. 10/535,025 in        the national stage thereof    -   U.S. Provisional Patent Application 60/448,807, filed Feb. 20,        2003, entitled, “Stimulation for treating autoimmune-related        disorders of the CNS”    -   U.S. Provisional Patent Application 60/461,232 to Gross et al.,        filed Apr. 8, 2003, entitled, “Treating abnormal conditions of        the mind and body by modifying properties of the blood-brain        barrier and cephalic blood flow”    -   PCT Patent Application PCT/IL03/00338 to Shalev, filed Apr. 25,        2003, which published as PCT Publication WO 03/090599, entitled,        “Methods and apparatus for modifying properties of the BBB and        cerebral circulation by using the neuroexcitatory and/or        neuroinhibitory effects of odorants on nerves in the head,” and        U.S. patent application Ser. No. 10/512,780, filed Oct. 25, 2004        in the national stage thereof, which published as US Patent        Application 2005/0266099    -   U.S. Provisional Patent Application 60/506,165, filed Sep. 26,        2003, entitled, “Diagnostic applications of stimulation”    -   U.S. patent application Ser. No. 10/678,730, filed Oct. 2, 2003,        entitled, “Targeted release of nitric oxide in the brain        circulation for opening the BBB,” which published as U.S. patent        application Ser. No. 2005/0074506, and PCT Patent Application        PCT/IL04/000911, filed Oct. 3, 2004, claiming priority        therefrom, which published as PCT Publication WO 05/030118    -   PCT Patent Application PCT/IL04/000897, filed Sep. 26, 2004,        entitled, “Stimulation for treating and diagnosing conditions,”        which published as PCT Publication WO 05/030025    -   U.S. Provisional Patent Application 60/604,037, filed Aug. 23,        2004, entitled, “Concurrent bilateral SPG modulation”    -   PCT Patent Application PCT/IL05/000912, filed Aug. 23, 2005,        entitled, “Concurrent bilateral SPG modulation,” which published        as PCT Publication WO 06/021957    -   U.S. patent application Ser. No. 10/952,536, filed Sep. 27,        2004, entitled, “Stimulation for treating and diagnosing        conditions,” which published as U.S. Patent Application        Publication 2005/0159790    -   U.S. patent application Ser. No. 11/349,020, filed Feb. 7, 2006,        which issued as U.S. Pat. No. 7,561,919, entitled, “SPG        stimulation via the greater palatine canal”

In an embodiment of the present invention, electrical stimulation system10 comprises circuitry described in one or more of the above-mentionedapplications.

In an embodiment of the present invention, an MTS is stimulated usingthe magnetic stimulation apparatus and methods described in theabove-mentioned U.S. patent application Ser. No. 10/783,113.

As used in the present application and in the claims, the BBB comprisesthe tight junctions opposing the passage of most ions and largemolecular weight compounds between the blood and brain tissue. As usedin the present application and in the claims, the BTB comprises abarrier opposing the passage of many ions and large molecular weightcompounds between the blood and tissue of a brain tumor.

It will be appreciated by persons skilled in the art that the presentinvention is not limited to what has been particularly shown anddescribed hereinabove. Rather, the scope of the present inventionincludes both combinations and subcombinations of the various featuresdescribed hereinabove, as well as variations and modifications thereofthat are not in the prior art, which would occur to persons skilled inthe art upon reading the foregoing description. For example, elementswhich are shown in a figure to be housed within one integral unit may,for some applications, be disposed in a plurality of distinct units.Similarly, apparatus for communication and power transmission which areshown to be coupled in a wireless fashion may, alternatively, be coupledin a wired fashion, and apparatus for communication and powertransmission which are shown to be coupled in a wired fashion may,alternatively, be coupled in a wireless fashion.

The invention claimed is:
 1. Apparatus for treating a subject,comprising: one or more electrodes, configured to be applied to a siteof the subject selected from the group consisting of: a sphenopalatineganglion (SPG), a greater palatine nerve, a lesser palatine nerve, asphenopalatine nerve, a communicating branch between a maxillary nerveand an SPG, an otic ganglion, an afferent fiber going into the oticganglion, an efferent fiber going out of the otic ganglion, aninfraorbital nerve, a vidian nerve, a greater superficial petrosalnerve, and a lesser deep petrosal nerve; and a control unit, configuredto: drive the one or more electrodes to apply electrical stimulation tothe site, and configure the stimulation to excite nervous tissue of thesite at a strength that (a) is sufficient to induce at least oneneuroprotective occurrence selected from the group consisting of: anincrease in cerebral blood flow (CBF) of the subject, and a release ofone or more neuroprotective substances, and (b) is insufficient toinduce a significant increase in permeability of a blood-brain barrier(BBB) of the subject.
 2. The apparatus according to claim 1, wherein thecontrol unit is configured to set the strength to less than 90% of astrength sufficient to induce the significant increase in thepermeability of the BBB.
 3. The apparatus according to claim 1, whereinthe control unit is configured to set the strength to less than 40% of astrength sufficient to induce the significant increase in thepermeability of the BBB.
 4. The apparatus according to claim 1, whereinthe control unit is configured to set the strength to more than 50% of astrength sufficient to induce the significant increase in thepermeability of the BBB.
 5. The apparatus according to claim 1, whereinthe site includes the SPG, and wherein the electrodes are configured tobe applied to the SPG.
 6. The apparatus according to claim 5, comprisingan elongated support element configured to be placed within a greaterpalatine canal of the subject, sized to extend from a palate of thesubject to the SPG, and having a distal end, wherein the electrodes arefixed to the support element in a vicinity of the distal end thereof. 7.The apparatus according to claim 1, wherein the control unit isconfigured to configure the stimulation to induce the at least oneneuroprotective occurrence without producing a measurably-harmfulclinical effect for the subject.